Journal articles on the topic 'Gene co-expression pattern'
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Roy, Swarup, Dhruba K. Bhattacharyya, and Jugal K. Kalita. "CoBi: Pattern Based Co-Regulated Biclustering of Gene Expression Data." Pattern Recognition Letters 34, no. 14 (October 2013): 1669–78. http://dx.doi.org/10.1016/j.patrec.2013.03.018.
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Muller, Heiko, and Francesco Acquati. "Topological Properties of Co-Occurrence Networks in Published Gene Expression Signatures." Bioinformatics and Biology Insights 2 (January 2008): BBI.S518. http://dx.doi.org/10.4137/bbi.s518.
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Meta-analysis of high-throughput gene expression data is often used for the interpretation of proprietary gene expression data sets. We have recently shown that co-occurrence patterns of gene expression in published cancer-related gene expression signatures are reminiscent of several cancer signaling pathways. Indeed, significant co-occurrence of up to ten genes in published gene expression signatures can be exploited to build a co-occurrence network from the sets of co-occurring genes (“co-occurrence modules”). Such co-occurrence network is represented by an undirected graph, where single genes are assigned to vertices and edges indicate that two genes are significantly co-occurring. Thus, graph-cut methods can be used to identify groups of highly interconnected vertices (“network communities”) that correspond to sets of genes that are significantly co-regulated in human cancer. Here, we investigate the topological properties of co-occurrence networks derived from published gene expression signatures and show that co-occurrence networks are characterized by scale-free topology and hierarchical modularity. Furthermore, we report that genes with a “promiscuous” or a “faithful” co-occurrence pattern can be distinguished. This behavior is reminiscent of date and party hubs that have been identified in protein-protein interaction networks.
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MA, PATRICK C. H., KEITH C. C. CHAN, and DAVID K. Y. CHIU. "CLUSTERING AND RE-CLUSTERING FOR PATTERN DISCOVERY IN GENE EXPRESSION DATA." Journal of Bioinformatics and Computational Biology 03, no. 02 (April 2005): 281–301. http://dx.doi.org/10.1142/s0219720005001053.
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The combined interpretation of gene expression data and gene sequences is important for the investigation of the intricate relationships of gene expression at the transcription level. The expression data produced by microarray hybridization experiments can lead to the identification of clusters of co-expressed genes that are likely co-regulated by the same regulatory mechanisms. By analyzing the promoter regions of co-expressed genes, the common regulatory patterns characterized by transcription factor binding sites can be revealed. Many clustering algorithms have been used to uncover inherent clusters in gene expression data. In this paper, based on experiments using simulated and real data, we show that the performance of these algorithms could be further improved. For the clustering of expression data typically characterized by a lot of noise, we propose to use a two-phase clustering algorithm consisting of an initial clustering phase and a second re-clustering phase. The proposed algorithm has several desirable features: (i) it utilizes both local and global information by computing both a "local" pairwise distance between two gene expression profiles in Phase 1 and a "global" probabilistic measure of interestingness of cluster patterns in Phase 2, (ii) it distinguishes between relevant and irrelevant expression values when performing re-clustering, and (iii) it makes explicit the patterns discovered in each cluster for possible interpretations. Experimental results show that the proposed algorithm can be an effective algorithm for discovering clusters in the presence of very noisy data. The patterns that are discovered in each cluster are found to be meaningful and statistically significant, and cannot otherwise be easily discovered. Based on these discovered patterns, genes co-expressed under the same experimental conditions and range of expression levels have been identified and evaluated. When identifying regulatory patterns at the promoter regions of the co-expressed genes, we also discovered well-known transcription factor binding sites in them. These binding sites can provide explanations for the co-expressed patterns.
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OLMAN, VICTOR, CHINDO HICKS, PENG WANG, and YING XU. "GENE EXPRESSION DATA ANALYSIS IN SUBTYPES OF OVARIAN CANCER USING COVARIANCE ANALYSIS." Journal of Bioinformatics and Computational Biology 04, no. 05 (October 2006): 999–1014. http://dx.doi.org/10.1142/s0219720006002296.
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Many studies have used microarray technology to identify the molecular signatures of human cancer, yet the critical features of these often unmanageably large set of signatures remain elusive. We have investigated co-expression pattern in four subtypes of ovarian cancer from 104 cancer patients using covariance analysis, treating each subtype of ovarian cancer as a distinct disease entity. We sought gene pairs that were transcriptionally co-expressed in one or multiple subtypes of ovarian cancer, establishing a high confidence network of 87 genes interconnected by significantly high co-expression links that were observed in at least two subtypes of ovarian cancer. We have shown that certain groups of co-expressed gene pairs are cancer subtype specific, through demonstrating significant differences in co-expression patterns of gene pairs between subtypes of ovarian cancer. In addition, we identified a set of 24 genes that classified patients into specific cancer subtypes with a misclassification error rate of less than 5%. Our findings illustrate how large public microarray gene expression datasets could be exploited for identification of cancer subtype specific molecular signatures, and how to classify cancer patients into specific subtypes of cancer using gene expression profiles.
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KUO, Ming-Wei, John POSTLETHWAIT, Wen-Chih LEE, Show-Wan LOU, Woon-Khiong CHAN, and Bon-chu CHUNG. "Gene duplication, gene loss and evolution of expression domains in the vertebrate nuclear receptor NR5A (Ftz-F1) family." Biochemical Journal 389, no. 1 (June 21, 2005): 19–26. http://dx.doi.org/10.1042/bj20050005.
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Fushi tarazu factor 1 (Ftz-F1, NR5A) is a zinc-finger transcription factor that belongs to the nuclear receptor superfamily and regulates genes that are involved in sterol and steroid metabolism in gonads, adrenals, liver and other tissues. To understand the evolutionary origins and developmental genetic relationships of the Ftz-F1 genes, we have cloned four homologous Ftz-f1 genes in zebrafish, called ff1a, ff1b, ff1c and ff1d. These four genes have different temporal and spatial expression patterns during development, indicating that they have distinct mechanisms of genetic regulation. Among them, the ff1a expression pattern is similar to mammalian Nr5a2, while the ff1b pattern is similar to that of mammalian Nr5a1. Genetic mapping experiments show that these four ff1 genes are located on chromosome segments conserved between the zebrafish and human genomes, indicating a common ancestral origin. Phylogenetic and conserved synteny analysis show that ff1a is the orthologue of NR5A2, and that ff1b and ff1d genes are co-orthologues of NR5A1 that arose by a gene-duplication event, probably a whole-genome duplication, in the ray-fin lineage, and each gene is located next to an NR6A1 co-orthologue as in humans, showing that the tandem duplication occurred before the divergence of human and zebrafish lineages. ff1c does not have a mammalian counterpart. Thus we have characterized the phylogenetic relationships, expression patterns and chromosomal locations of these Ftz-F1 genes, and have demonstrated their identities as NR5A genes in relation to the orthologous genes in other species.
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Raja, Komal K. B., Evan A. Bachman, Catrina E. Fernholz, David S. Trine, Rebecca E. Hobmeier, Nathaniel J. Maki, Timothy J. Massoglia, and Thomas Werner. "The Genetic Mechanisms Underlying the Concerted Expression of the yellow and tan Genes in Complex Patterns on the Abdomen and Wings of Drosophila guttifera." Genes 14, no. 2 (January 24, 2023): 304. http://dx.doi.org/10.3390/genes14020304.
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How complex morphological patterns form is an intriguing question in developmental biology. However, the mechanisms that generate complex patterns remain largely unknown. Here, we sought to identify the genetic mechanisms that regulate the tan (t) gene in a multi-spotted pigmentation pattern on the abdomen and wings of Drosophila guttifera. Previously, we showed that yellow (y) gene expression completely prefigures the abdominal and wing pigment patterns of this species. In the current study, we demonstrate that the t gene is co-expressed with the y gene in nearly identical patterns, both transcripts foreshadowing the adult abdominal and wing melanin spot patterns. We identified cis-regulatory modules (CRMs) of t, one of which drives reporter expression in six longitudinal rows of spots on the developing pupal abdomen, while the second CRM activates the reporter gene in a spotted wing pattern. Comparing the abdominal spot CRMs of y and t, we found a similar composition of putative transcription factor binding sites that are thought to regulate the complex expression patterns of both terminal pigmentation genes y and t. In contrast, the y and t wing spots appear to be regulated by distinct upstream factors. Our results suggest that the D. guttifera abdominal and wing melanin spot patterns have been established through the co-regulation of y and t, shedding light on how complex morphological traits may be regulated through the parallel coordination of downstream target genes.
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Liu, Guo, Yaojian Xie, Xiuhua Shang, and Zhihua Wu. "Expression Patterns and Gene Analysis of the Cellulose Synthase Gene Superfamily in Eucalyptus grandis." Forests 12, no. 9 (September 15, 2021): 1254. http://dx.doi.org/10.3390/f12091254.
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Cellulose is the world’s most abundant renewable energy resource, and a variety of cellulose synthase genes are involved in the biosynthesis of cellulose. In the process of cellulose synthesis, all cellulose synthases are interrelated and act synergistically. In this study, we analyzed the contents of cellulose, hemicellulose, and lignin in the different parts and tissues of E. grandis. The results showed that the cellulose content had greater differences among three different heights. On this basis, we carried out the transcriptome-wide profiling of gene expression patterns using RNA sequencing. A total of 2066 differentially expressed genes were identified for three pairwise comparisons between three different heights, most of which were related to the programmed photosynthetic membrane and photosystem. A total of 100 transcripts of CSs (58 CesA and 42 Csl) were obtained from transcriptome libraries. The expression pattern of these genes indicated that different CS genes had a wide range of expression profiles. A phylogenetic analysis of 135 reference CS genes showed that the CSs of E. grandis were clustered into six major groups (CesA1-9, CslA, CslB/H, CslD, CslE, and CslG). Based on the weighted gene co-expression network analysis, a dual-directional regulation mechanism between Csl and CesA proteins in the cellulose biosynthesis was identified. The gene expression profile analysis, using qRT-PCR in different tissues of E. grandis, demonstrated that the CSs were highly expressed in xylem, and CesAs had a higher relative expression than Csls. The analysis of sequence similarity combined with the expression pattern indicated that the CesA1, 3, and 6 transcripts were associated with the biosynthesis of the secondary cell wall, and CesA4, 5, and 7 transcripts were more likely to associate with the biosynthesis of the primary cell wall. Finally, the qRT-PCR analysis confirmed the expression of 11 selected CSs in three different parts of E. grandis.
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Donizetti, Aldo, Marcella Fiengo, Sergio Minucci, and Francesco Aniello. "Duplicated zebrafish relaxin-3 gene shows a different expression pattern from that of the co-orthologue gene." Development, Growth & Differentiation 51, no. 8 (September 23, 2009): 715–22. http://dx.doi.org/10.1111/j.1440-169x.2009.01131.x.
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Ma, Shisong, Smit Shah, Hans J. Bohnert, Michael Snyder, and Savithramma P. Dinesh-Kumar. "Incorporating Motif Analysis into Gene Co-expression Networks Reveals Novel Modular Expression Pattern and New Signaling Pathways." PLoS Genetics 9, no. 10 (October 3, 2013): e1003840. http://dx.doi.org/10.1371/journal.pgen.1003840.
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Rattay, Kristin, Hannah Verena Meyer, Philip Brennecke, Alejandro Reyes, Sheena Pinto, Benedikt Brors, Wolfgang Huber, Lars Steinmetz, and Bruno Kyewski. "Thymic expression of tissue-restricted self-antigens is a highly coordinated and evolutionary conserved process." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 186.15. http://dx.doi.org/10.4049/jimmunol.196.supp.186.15.
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Abstract Promiscuous gene expression (pGE) of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential for tolerance imposition in the thymus. PGE is characterized on the one hand by inclusion of a broad range of TRAs and on the other hand by its mosaic patterns, whereby each antigen is only expressed in 1–3% of mTECs at a given point in time. Yet, this mosaic pattern at the single cell level faithfully adds up to the full repertoire of self-antigens at the population level. In order to analyze the regulatory mechanisms underlying this transcriptional heterogeneity among mTECs, we applied two complementing approaches, the isolation of minor mTEC subsets as defined by TRA-selected gene co-expression groups in conjunction with single cell mRNA sequencing. Different TRA-selected mTEC subfractions, each expressing distinct sets of genes in a mutually overlapping fashion, mapped to distinct stages of mTEC development. These co-expression patterns were evolutionary conserved between mouse and human (Rattay et al., J. Autoimmunity 2015). Applying an unbiased single cell mRNA sequencing approach, we extended these findings to the single cell level and showed that the mouse mTEC population essentially represents a composite of multiple co-expression groups (Brennecke et al., Nat. Immunology 2015). These co-expression groups may represent only snapshots of a continuum of changing co-expression groups along the lifetime of an individual mTEC, as captured in the model of “sliding co-expression groups” (Pinto et al., PNAS 2013). Continuous genome scanning would potentially enlarge the overall diversity of self-antigens displayed by a single mTEC.
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Spirov, Alexander V., Marat A. Sabirov, and David M. Holloway. "In SilicoEvolution of Gene Cooption in Pattern-Forming Gene Networks." Scientific World Journal 2012 (2012): 1–19. http://dx.doi.org/10.1100/2012/560101.
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Gene recruitment or cooption occurs when a gene, which may be part of an existing gene regulatory network (GRN), comes under the control of a new regulatory system. Such re-arrangement of pre-existing networks is likely more common for increasing genomic complexity than the creation of new genes. Using evolutionary computations (EC), we investigate how cooption affects the evolvability, outgrowth and robustness of GRNs. We use a data-driven model of insect segmentation, for the fruit fly Drosophila, and evaluate fitness by robustness to maternal variability—a major constraint in biological development. We compare two mechanisms of gene cooption: a simpler one with gene Introduction and Withdrawal operators; and one in which GRN elements can be altered by transposon infection. Starting from a minimal 2-gene network, insufficient for fitting the Drosophila gene expression patterns, we find a general trend of coopting available genes into the GRN, in order to better fit the data. With the transposon mechanism, we find co-evolutionary oscillations between genes and their transposons. These oscillations may offer a new technique in EC for overcoming premature convergence. Finally, we comment on how a differential equations (in contrast to Boolean) approach is necessary for addressing realistic continuous variation in biochemical parameters.
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Josyula, Navya, Melvin E. Andersen, Norbert E. Kaminski, Edward Dere, Timothy R. Zacharewski, and Sudin Bhattacharya. "Gene co-regulation and co-expression in the aryl hydrocarbon receptor-mediated transcriptional regulatory network in the mouse liver." Archives of Toxicology 94, no. 1 (November 14, 2019): 113–26. http://dx.doi.org/10.1007/s00204-019-02620-5.
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AbstractFour decades after its discovery, the aryl hydrocarbon receptor (AHR), a ligand-inducible transcription factor (TF) activated by the persistent environmental contaminant 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), remains an enigmatic molecule with a controversial endogenous role. Here, we have assembled a global map of the AHR gene regulatory network in female C57BL/6 mice orally gavaged with 30 µg/kg of TCDD from a combination of previously published gene expression and genome-wide TF-binding data sets. Using Kohonen self-organizing maps and subspace clustering, we show that genes co-regulated by common upstream TFs in the AHR network exhibit a pattern of co-expression. Directly bound, indirectly bound, and non-genomic AHR target genes exhibit distinct expression patterns, with the directly bound targets associated with highest median expression. Interestingly, among the directly bound AHR target genes, the expression level increases with the number of AHR-binding sites in the proximal promoter regions. Finally, we show that co-regulated genes in the AHR network activate distinct groups of downstream biological processes. Although the specific findings described here are restricted to hepatic effects under short-term TCDD exposure, this work describes a generalizable approach to the reconstruction and analysis of transcriptional regulatory cascades underlying cellular stress response, revealing network hierarchy and the nature of information flow from the initial signaling events to phenotypic outcomes. Such reconstructed networks can form the basis of a new generation of quantitative adverse outcome pathways.
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Ahi, Ehsan Pashay, Emmanouil Tsakoumis, Mathilde Brunel, and Monika Schmitz. "Transcriptional study reveals a potential leptin-dependent gene regulatory network in zebrafish brain." Fish Physiology and Biochemistry 47, no. 4 (July 8, 2021): 1283–98. http://dx.doi.org/10.1007/s10695-021-00967-0.
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AbstractThe signal mediated by leptin hormone and its receptor is a major regulator of body weight, food intake and metabolism. In mammals and many teleost fish species, leptin has an anorexigenic role and inhibits food intake by influencing the appetite centres in the hypothalamus. However, the regulatory connections between leptin and downstream genes mediating its appetite-regulating effects are still not fully explored in teleost fish. In this study, we used a loss of function leptin receptor zebrafish mutant and real-time quantitative PCR to assess brain expression patterns of several previously identified anorexigenic genes downstream of leptin signal under different feeding conditions (normal feeding, 7-day fasting, 2 and 6-h refeeding). These downstream factors include members of cart genes, crhb and gnrh2, as well as selected genes co-expressed with them based on a zebrafish co-expression database. Here, we found a potential gene expression network (GRN) comprising the abovementioned genes by a stepwise approach of identifying co-expression modules and predicting their upstream regulators. Among the transcription factors (TFs) predicted as potential upstream regulators of this GRN, we found expression pattern of sp3a to be correlated with transcriptional changes of the downstream gene network. Interestingly, the expression and transcriptional activity of Sp3 orthologous gene in mammals have already been implicated to be under the influence of leptin signal. These findings suggest a potentially conserved regulatory connection between leptin and sp3a, which is predicted to act as a transcriptional driver of a downstream gene network in the zebrafish brain.
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Hao, Pei, Yao Yu, XiaoYan Zhang, Kang Tu, HaiWei Fan, and Yang Zhong. "The contribution of cis-regulatory elements to head-to-head gene pairs’ co-expression pattern." Science in China Series C: Life Sciences 52, no. 1 (January 2009): 74–79. http://dx.doi.org/10.1007/s11427-009-0004-9.
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Teofili, Luciana, Eugenia Rosa Nuzzolo, Maurizio Martini, Maria Teresa Voso, Sara Capodimonti, Valeriana Cocomazzi, Maria Grazia Iachininoto, Gina Zini, and Luigi M. Larocca. "The Contact with MDS Endothelial Cells Alters the Pattern of Lineage-Specific Gene Expression During Normal Hematopoietic Differentiation." Blood 120, no. 21 (November 16, 2012): 1718. http://dx.doi.org/10.1182/blood.v120.21.1718.1718.
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Abstract Abstract 1718 In the embryo, hematopoiesis and angiogenesis occur concurrently, since endothelial and hematopoietic cells derive from a common cell precursor, the hemangioblast. In the post natal life, the bone marrow (BM) vascular niche has an important role in supporting hematopoietic stem cells (HSC) proliferation and differentiation. Moreover, during the processes of homing and mobilization, BM vascular niche regulates HSC migration. In BM failure, these functions are promoted by vascular niches located outside of the BM, such as in the spleen, thus confirming that endothelial cells are relevant to the normal hematopoietic differentiation. The dominant feature of myelodyspslatic syndromes (MDS) is the impaired capacity of HSC to give rise to a terminally differentiated normal cell population in one or more lineages. We hypothesized that in MDS patients the vascular niches within and eventually outside of the BM might be altered and that they do not support adequately the physiologic hematopoietic differentiation, thus contributing to the pathogenesis of the disease. To investigate this hypothesis, we isolated and expanded endothelial colony forming cells (ECFCs) (Ingram et al. Blood. 2004;104: 2752) from the peripheral blood of patients with MDS (RCMD) and we used ECFCs as a surrogate of the vascular niche to differentiate hematopoietic cells. Normal CD34+ were seeded over a layer of endothelial cells and cultured for 8 days in different cytokine- containing media able to induce selective granulocytic-macrophage, erythroid or megakaryocyte differentiation. At baseline and after 5 and 8 days of co-culture, hematopoietic cells were recovered by gentle repeated washings, and then they were analyzed with RT-PCR for the expression of lineage specific genes. For each lineage, two genes, mainly involved either in the early or in the late phase of the differentiation, respectively, were analyzed. Basically, we found that co-culturing CD34+ cells in contact with a normal endothelial layer the gene expression observed in the corresponding no-layer cultures was amplified. This effect was strictly dependent on the physical contact between hematopoietic and endothelial cells, since it was abolished when cells were grown separated from a porous membrane. We observed that in co-cultures with normal hematopoietic cells and MDS ECFCs, the modulatory effect exerted by the endothelial layer was partially or completely lost. For example, CD34+ cells undergoing granulocyte differentiation showed a progressive decline of PU.1 gene expression, followed by the rise of the expression of MPO gene; these effects were much more evident if cells were cultured over normal ECFCs. In contrast, this pattern of gene expression was deeply perturbed when normal CD34+ cells were cultured with MDS ECFCs: actually, at day 7, the PU.1 RNA level was six folds higher and the MPO RNA level was three folds lower than that observed in co-cultures with normal ECFCs. Similar figures were observed for RUNX1 and GP1b gene expression in cells undergoing megakaryocyte differentiation. Moreover, CD34+ cells undergoing erythroid differentiation on normal ECFCs exhibited the progressive up-regulation of FOG-1 and of transferrin receptor (TFR) gene expression: interestingly, the co-culture with MDS ECFCs resulted in a lower expression of FOG -1 gene but also in a surprisingly higher expression of the TFR gene. Overall, these data suggest that in MDS does exist an impairment of talking between endothelial and hematopoietic cells. To understand which molecular pathways are involved could represent the basis for a novel therapy approach. Disclosures: No relevant conflicts of interest to declare.
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McCarthy, Erin, Aaron Barron, Noelia Morales-Prieto, Martina Mazzocchi, Cathal M. McCarthy, Louise M. Collins, Aideen M. Sullivan, and Gerard W. O’Keeffe. "Gene Co-expression Analysis of the Human Substantia Nigra Identifies ZNHIT1 as an SNCA Co-expressed Gene that Protects Against α-Synuclein-Induced Impairments in Neurite Growth and Mitochondrial Dysfunction in SH-SY5Y Cells." Molecular Neurobiology 59, no. 5 (February 17, 2022): 2745–57. http://dx.doi.org/10.1007/s12035-022-02768-9.
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AbstractParkinson’s disease (PD) is neurodegenerative disorder with the pathological hallmarks of progressive degeneration of midbrain dopaminergic neurons from the substantia nigra (SN), and accumulation and spread of inclusions of aggregated α-synuclein (α-Syn). Since current PD therapies do not prevent neurodegeneration, there is a need to identify therapeutic targets that can prevent α-Syn-induced reductions in neuronal survival and neurite growth. We hypothesised that genes that are normally co-expressed with the α-Syn gene (SNCA), and whose co-expression pattern is lost in PD, may be important for protecting against α-Syn-induced dopaminergic degeneration, since broken correlations can be used as an index of functional misregulation. Gene co-expression analysis of the human SN showed that nuclear zinc finger HIT-type containing 1 (ZNHIT1) is co-expressed with SNCA and that this co-expression pattern is lost in PD. Overexpression of ZNHIT1 was found to increase deposition of the H2A.Z histone variant in SH-SY5Y cells, to promote neurite growth and to prevent α-Syn-induced reductions in neurite growth and cell viability. Analysis of ZNHIT1 co-expressed genes showed significant enrichment in genes associated with mitochondrial function. In agreement, bioenergetic state analysis of mitochondrial function revealed that ZNHIT1 increased cellular ATP synthesis. Furthermore, α-Syn-induced impairments in basal respiration, maximal respiration and spare respiratory capacity were not seen in ZNHIT1-overexpressing cells. These data show that ZNHIT1 can protect against α-Syn-induced degeneration and mitochondrial dysfunction, which rationalises further investigation of ZNHIT1 as a therapeutic target for PD.
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Singh, Pushpa, and Narendra Singh. "Role of Data Mining Techniques in Bioinformatics." International Journal of Applied Research in Bioinformatics 11, no. 1 (January 2021): 51–60. http://dx.doi.org/10.4018/ijarb.2021010106.
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Data mining offers a highly effective technique that is useful in research and development of bioinformatics. Bioinformatics consists biological information such as DNA, RNA, and protein. Data mining tasks/techniques are classification, prediction, clustering, association, outlier detection, regression, and pattern tracking. Data mining provides important correlation, hidden patterns, and knowledge from the bioinformatics data set. This paper presents the role of data mining techniques in bioinformatics application. Classification of gene and protein structure, analyzing the gene expression, association of co-disease, outlier detection and gene selection, protein structure prediction, and drug discovery are some typical biological example that has proven data mining as a suitable technique for bioinformatics.
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Rashmi, Richa, and Sharmistha Majumdar. "Pan-Cancer Analysis Reveals the Prognostic Potential of the THAP9/THAP9-AS1 Sense–Antisense Gene Pair in Human Cancers." Non-Coding RNA 8, no. 4 (July 8, 2022): 51. http://dx.doi.org/10.3390/ncrna8040051.
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Human THAP9, which encodes a domesticated transposase of unknown function, and lncRNA THAP9-AS1 (THAP9-antisense1) are arranged head-to-head on opposite DNA strands, forming a sense and antisense gene pair. We predict that there is a bidirectional promoter that potentially regulates the expression of THAP9 and THAP9-AS1. Although both THAP9 and THAP9-AS1 are reported to be involved in various cancers, their correlative roles on each other’s expression has not been explored. We analyzed the expression levels, prognosis, and predicted biological functions of the two genes across different cancer datasets (TCGA, GTEx). We observed that although the expression levels of the two genes, THAP9 and THAP9-AS1, varied in different tumors, the expression of the gene pair was strongly correlated with patient prognosis; higher expression of the gene pair was usually linked to poor overall and disease-free survival. Thus, THAP9 and THAP9-AS1 may serve as potential clinical biomarkers of tumor prognosis. Further, we performed a gene co-expression analysis (using WGCNA) followed by a differential gene correlation analysis (DGCA) across 22 cancers to identify genes that share the expression pattern of THAP9 and THAP9-AS1. Interestingly, in both normal and cancer samples, THAP9 and THAP9-AS1 often co-express; moreover, their expression is positively correlated in each cancer type, suggesting the coordinated regulation of this H2H gene pair.
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Henderson, Gregory S., Paul J. van Diest, Horst Burger, Jose Russo, and Venu Raman. "Expression Pattern of a Homeotic Gene, HOXA5, in Normal Breast and in Breast Tumors." Analytical Cellular Pathology 28, no. 5-6 (January 1, 2006): 305–13. http://dx.doi.org/10.1155/2006/974810.
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Introduction: Homeotic (HOX) gene products are now known to be functionally associated with breast cancer biogenesis. Recent evidence has indicated that HOXA5 regulates both p53 and progesterone receptor expression levels in breast cancer cells. In addition, HOXA5 has been shown to interact and regulate the activity of another protein referred to as Twist. As homeotic genes play a pivotal role in development, we sought to decipher the expression pattern in both normal breast tissues and in breast carcinomas. Methods: RT-PCR and immunohistochemistry were performed, to assay the levels of HOXA5 expression, on a panel of normal breast tissue and its corresponding primary breast tumors. Results and Conclusions: We show that HOXA5 expression was maintained at stable levels at different reproductive stages of a woman's life, except during lactation. This evidence indicates that HOXA5 may play a role in maintaining the differentiated state within the breast epithelium. However, nearly 70% of all breast carcinomas had decreased HOXA5 protein levels as compared to normal breast tissues. In addition, we demonstrate that HOXA5 protein expression levels in breast carcinomas inversely co-relates with Epidermal Growth Factor Receptor (EGFR) expression. Furthermore, we found that the survival rate amongst the different low levels of HOXA5 expressing breast tumors was not significant, indicative of an early tumorigenesis process in the absence of innate levels of HOXA5 in normal breast cells.
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Thomalla, Miriam, Andreas Schmid, Julia Hehner, Sebastian Koehler, Elena Neumann, Ulf Müller-Ladner, Andreas Schäffler, and Thomas Karrasch. "Toll-like Receptor 7 (TLR7) Is Expressed in Adipocytes and the Pharmacological TLR7 Agonist Imiquimod and Adipocyte-Derived Cell-Free Nucleic Acids (cfDNA) Regulate Adipocyte Function." International Journal of Molecular Sciences 23, no. 15 (July 30, 2022): 8475. http://dx.doi.org/10.3390/ijms23158475.
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Endosome-localized Toll-like receptors (TLRs) 3 and 9 are expressed and functionally active in adipocytes. The functionality and role of TLR7 in adipocyte biology and innate immunity of adipose tissue (AT) is poorly characterized. We analyzed TLR7 mRNA and protein expression in murine 3T3-L1 and primary adipocytes, in co-cultures of 3T3-L1 adipocytes with murine J774A.1 monocytes and in human AT. The effects of TLR7 agonists imiquimod (IMQ) and cell-free nucleic acids (cfDNA) on adipokine concentration in cell-culture supernatants and gene expression profile were investigated. We found that TLR7 expression is strongly induced during adipocyte differentiation. TLR7 gene expression in adipocytes and AT stroma-vascular cells (SVC) seems to be independent of TLR9. IMQ downregulates resistin concentration in adipocyte cell-culture supernatants and modulates gene expression of glucose transporter Glut4. Adipocyte-derived cfDNA reduces adiponectin and resistin in cell-culture supernatants and potentially inhibits Glut4 gene expression. The responsiveness of 3T3-L1 adipocytes to imiquimod is preserved in co-culture with J774A.1 monocytes. Obesity-related, adipocyte-derived cfDNA engages adipocytic pattern recognition receptors (PRRs), modulating AT immune and metabolic homeostasis during adipose inflammation.
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Yan, Cunyao, Kai Jia, Jing Zhang, Zhonglin Xiao, Xiaomei Sha, Jie Gao, and Huizhuan Yan. "Genome-wide identification and expression pattern analysis of lipoxygenase gene family in turnip (Brassica rapa L. subsp. rapa)." PeerJ 10 (July 22, 2022): e13746. http://dx.doi.org/10.7717/peerj.13746.
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Turnip (Brassica rapa L. subsp. rapa) is an important crop with edible and medicinal values, and various stresses, especially salt stress and drought stress, seriously threaten the yield of turnips. LOXs play important roles in regulating plant growth and development, signal transduction, and biotic and abiotic stress responses through secondary metabolites produced by the oxylipin metabolic pathway, and although the turnip genome has been published, however, the role of LOX family genes in various abiotic stress responses has not been systematically studied in turnips. In this study, a total of 15 LOX genes (BrrLOX) were identified in turnip, distributed on six chromosomes. Phylogenetic tree analysis classified these LOX genes into two classes: three 9-LOX proteins and 12 13-LOX type II proteins. Gene duplication analysis showed that tandem and segmental duplication were the main pathways for the expansion of the BrrLOX gene family. The Ka and Ks values of the duplicated genes indicate that the BrrLOX gene underwent strong purifying selection. Further analysis of the cis-acting elements of the promoters suggested that the expression of the BrrLOX gene may be influenced by stress and phytohormones. Transcriptome data analysis showed that 13 BrrLOX genes were expressed at one or more stages of turnip tuber development, suggesting that LOX genes may be involved in the formation of turnip fleshy roots. The qRT-PCR analysis showed that four stresses (salt stress, drought stress, cold stress, and heat stress) and three hormone treatments (methyl jasmonate, salicylic acid, and abscisic acid) affected the expression levels of BrrLOX genes and that different BrrLOX genes responded differently to these stresses. In addition, weighted gene co-expression network analysis (WGCNA) of BrrLOX revealed seven co-expression modules, and the genes in these co-expression modules are collectively involved in plant growth and development and stress response processes. Thus, our results provide valuable information for the functional identification and regulatory mechanisms of BrrLOX in turnip growth and development and stress response.
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Cizelj, Ivanka, Daliborka Dušanić, Dušan Benčina, and Mojca Narat. "Mycoplasma and host interaction: In vitro gene expression modulation in Mycoplasma synoviae and infected chicken chondrocytes." Acta Veterinaria Hungarica 64, no. 1 (March 2016): 26–37. http://dx.doi.org/10.1556/004.2016.003.
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The complex interplay between Mycoplasma synoviae and chicken chondrocytes (CCH), which come into direct contact during infectious synovitis, has been examined at the level of gene expression. Our previous studies demonstrated a significant influence of M. synoviae on the level of CCH gene expression. Here, we show for the first time that in vitro co-cultivation of M. synoviae and CCH also induces upregulation of gene expression in this mycoplasma. We observed significantly increased expression of genes important for M. synoviae pathogenicity, including cysteine protease cysP, neuraminidase nanH, haemagglutinin vlhA, and the putative nuclease MS53_0284. Moreover, the pattern of gene expression was dependent on the infection environment. In CCH, significant changes in the expression of genes encoding catabolic enzymes of the cartilage extracellular matrix (cathepsins B, K and L, aggrecanase ADAM10, and matrix metalloproteinase MMP2) were demonstrated. Infection of CCH with M. synoviae also elevated the expression of the gene encoding peptidyl arginine deiminase, type III (PADI3), which is responsible for the post-translational citrullination of proteins.
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Salaverria, Itziar, Idoia Martin-Guerrero, Rabea Wagener, Markus Kreuz, Christian W. Kohler, Julia Richter, Barbara Pienkowska-Grela, et al. "A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma." Blood 123, no. 8 (February 20, 2014): 1187–98. http://dx.doi.org/10.1182/blood-2013-06-507996.
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Key Points A subset of lymphomas with gene expression and pathological characteristics of Burkitt lymphomas but absence of MYC translocation does exist. These lymphomas carry chr 11q proximal gains and telomeric losses, suggesting co-deregulation of oncogenes and tumor suppressor genes.
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Fang, Difeng, Rama Krishna Gurram, Kairong Cui, Chao Zhong, Gangqing Hu, Andrew Oler, Suveena Sharma, et al. "Bcl11b, a novel GATA3-interacting protein, regulates T-helper-2-cell differentiation and function." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 223.13. http://dx.doi.org/10.4049/jimmunol.198.supp.223.13.
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Abstract GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. Fine-tuning GATA3 transcription activity is critical for effectively expelling extracellular parasites and preventing allergic disorders. However, it is still elusive how GATA3 function is regulated in Th2 cells. Here, we report that the transcription factor B-cell Lymphoma 11b (Bcl11b) is a novel component of the GATA3 transcriptional complex executing GATA3-mediated gene expression. Bcl11b binds to GATA3 through protein-protein interaction; ChIP-Seq analysis showed co-localization of Bcl11b and GATA3 at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5 and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3 dependent indicating that Bcl11b inhibits GATA3-mediated cytokines production. Genome-wide analysis of Bcl11b- and GATA3-mediated gene regulation (RNA-Seq) and co-binding pattern (ChIP-Seq) suggests that GATA3/Bcl11b complex are involved in limiting Th2 gene expression as well as inhibiting non-Th2 gene expression. Thus, Bcl11b, a previously unknown GATA3 binding protein, fine-tunes GATA3-mediated gene expression in Th2 cells.
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Chen, Xin, Lingling Hu, Yuan Wang, Weijun Sun, and Chao Yang. "Single Cell Gene Co-Expression Network Reveals FECH/CROT Signature as a Prognostic Marker." Cells 8, no. 7 (July 10, 2019): 698. http://dx.doi.org/10.3390/cells8070698.
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Aberrant activation of signaling pathways is frequently observed and reported to be associated with the progression and poor prognosis of prostate cancer (PCa). We aimed to identify key biological processes regulated by androgen receptor (AR) using gene co-expression network from single cell resolution. The bimodal index was used to evaluate whether two subpopulations exist among the single cells. Gene expression among single cells revealed averaging pitfalls and bimodality pattern. Weighted gene co-expression network analysis (WGCNA) was used to identify modules of highly correlated genes. Twenty-nine gene modules were identified and AR-regulated modules were screened by significantly overlapping reported androgen induced differentially expressed genes. The biological function “generation of precursor metabolites and energy” was significantly enriched by AR-regulated modules with bimodality, presenting differential androgen response among subpopulations. Integrating with public ChIP-seq data, two genes FECH, and CROT has AR binding sites. Public in vitro studies also show that androgen regulates FECH and CROT. After receiving androgen deprivation therapy, patients lowly express FECH and CROT. Further survival analysis indicates that FECH/CROT signature can predict PCa recurrence. We reveal the heterogeneous function of “generation of precursor metabolites and energy” upon androgen stimulation from the perspective of single cells. Inhibitors targeting this biological process will facilitate to prevent prostate cancer progression.
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Wei, LN, CH Lee, P. Filipcik, and L. Chang. "Regulation of the mouse cellular retinoic acid-binding protein-I gene by thyroid hormone and retinoids in transgenic mouse embryos and P19 cells." Journal of Endocrinology 155, no. 1 (October 1, 1997): 35–46. http://dx.doi.org/10.1677/joe.0.1550035.
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The regulation of mouse cellular retinoic acid-binding protein-I (CRABP-I) gene expression by the retinoids and thyroid hormones was examined, by using a beta-galactosidase (lacZ) reporter gene and a CRABP-I specific antibody, in transgenic mouse embryos and a mouse embryonal carcinoma cell line P19. The CRABP-lacZ reporter gene expression recapitulated the expression pattern of endogenous CRABP-I in the developing central nervous system. In mid-gestation mouse embryos the expression of both the transgene and the endogenous protein was elevated under the condition of hypovitaminosis A, suggesting that depletion of retinoic acid (RA) induced CRABP-I expression in embryos. Consistently, this reporter was suppressed by RA in P19 cells. In co-transfection experiments it was demonstrated that the expression of RAR beta, RAR gamma or RXR alpha suppressed this reporter expression. In experiments designed to alter the thyroid hormone status in animals it was demonstrated that both the reporter gene and the endogenous CRABP-I expression were reduced by triiodothyronine injection and were elevated in a hypothyroidic condition induced by feeding with iodine-deficient diet supplemented with 6-propyl-2-thiouracil. In co-transfection experiments it was also demonstrated that the expression of T3R beta suppressed the reporter expression in P19 cells. It was concluded that RA had a suppressive effect on CRABP-I gene expression in embryos and P19 cells and the effect could be mediated through RAR beta, RAR gamma or RXR alpha. A role of thyroid hormones in CRABP-I gene expression and vitamin A metabolism in animals is discussed.
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Simon, H. G., R. Kittappa, P. A. Khan, C. Tsilfidis, R. A. Liversage, and S. Oppenheimer. "A novel family of T-box genes in urodele amphibian limb development and regeneration: candidate genes involved in vertebrate forelimb/hindlimb patterning." Development 124, no. 7 (April 1, 1997): 1355–66. http://dx.doi.org/10.1242/dev.124.7.1355.
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In certain urodeles, a lost appendage, including hand and foot, can be completely replaced through epimorphic regeneration. The regeneration process involves cellular activities similar to those described for embryogenesis. Working on the assumption that the morphological pattern specific for a forelimb or a hindlimb is controlled by different gene activities in the two limbs, we employed a mRNA differential display screen for the detection of candidate limb identity genes. Using this approach, we have isolated a newt gene which in regenerating and developing limbs reveals properties expected of a gene having a role in controlling limb morphology: (1) it is exclusively expressed in the forelimbs, but not hindlimbs, (2) during embryonic development its expression is co-incident with forelimb bud formation, (3) it has an elevated message level throughout the undifferentiated limb bud and the blastema, respectively, and (4) it is expressed only in mesenchymal, but not in epidermal tissues. This novel newt gene shares a conserved DNA-binding domain, the T-box, with putative transcription factors including the Brachyury (T) gene product. In a following PCR-based screen, we used the evolutionarily conserved T-box motif and amplified a family of related genes in the newt; their different expression patterns in normal and regenerating forelimbs, hindlimbs and tail suggest, in general, an important role of T-domain proteins in vertebrate pattern formation.
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Deyerle, K. L., J. E. Sims, S. K. Dower, and M. A. Bothwell. "Pattern of IL-1 receptor gene expression suggests role in noninflammatory processes." Journal of Immunology 149, no. 5 (September 1, 1992): 1657–65. http://dx.doi.org/10.4049/jimmunol.149.5.1657.
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Abstract The cytokine IL-1 can be elaborated by most nucleated cell types and exerts its pleiotropic effects on a variety of tissues through binding to its cognate receptor. Two forms of IL-1R, designated types I and II, have been identified. These proteins share limited amino acid identity but both bind IL-1 alpha and IL-1 beta. A large number of cell types have been shown to possess IL-1R in vitro, but few studies have addressed the question of in vivo expression. Using in situ hybridization in normal adult BALB/c mice, we have examined the tissue distributions of both IL-1R types. The results demonstrate that although lymphoid tissues in healthy animals express low or nondetectable levels of receptor transcript, nonlymphoid tissues constitutively express readily detectable levels of IL-1R mRNA. Thymus and spleen samples were largely negative for both IL-1R types I and II, whereas half of the lymph nodes examined expressed IL-1R type I. In nonlymphoid tissues, IL-1R type I transcript was detected in the dentate gyrus of the brain, endocrine pancreas, cardiac endothelium, epidermis, dermis, hair follicle epithelium, uterine serosa, vaginal stroma, vaginal squamous epithelium, developing oocytes, and granulosa cells of ruptured follicles. In contrast, the IL-1R type II probe hybridized to epidermis, dermis, and vaginal basal epithelium. The two types of IL-1R were rarely, if ever, co-expressed by the same cell. The distributional segregation of the receptor types and the expression of IL-1R in normal nonlymphoid tissues has broad implications for the role of IL-1 in homeostatic physiology.
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Iacobucci, Ilaria, Manja Meggendorfer, Niroshan Nadarajah, Stanley Pounds, Lei Shi, Chunxu Qu, Constance Baer, et al. "Integrated Transcriptomic and Genomic Sequencing Identifies Prognostic Constellations of Driver Mutations in Acute Myeloid Leukemia and Myelodysplastic Syndromes." Blood 134, Supplement_2 (November 21, 2019): LBA—4—LBA—4. http://dx.doi.org/10.1182/blood-2019-132746.
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CG Mullighan and T Haferlach: are co-senior authors Introduction: Recent genomic sequencing studies have advanced our understanding of the pathogenesis of myeloid malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and improved classification of specific subgroups. Unfortunately, these studies have mostly analyzed specific subtypes and/or used targeted DNA-sequencing, thus limiting discovery of novel mutational patterns and gene expression clusters. Here, we performed an integrated genome-wide mutational/transcriptomic analysis of a large cohort of adult AML and MDS samples to accurately define subtypes of diagnostic, prognostic and therapeutic relevance. Methods: We performed unbiased whole genome (WGS) and transcriptome sequencing (RNA-seq) of 1,304 adult individuals (598 AML and 706 MDS; Fig. 1A), incorporating analysis of somatic and presumed germline sequence mutations, chimeric fusions and structural complex variations. Transcriptomic gene expression data were processed by a rigorous bootstrap procedure to define gene expression subgroups in an unsupervised manner. Associations between genetic variants, gene expression groups and outcome were examined. Results: Genomic/transcriptome sequencing confirmed diagnosis according to WHO 2016 of AML with recurrent genetic abnormalities in 10.9% of cases. These cases had a distinct gene expression profile (Fig. 1A), good prognosis (Fig. 1B) and a combination of mutations in the following genes: KIT, ZBTB7A, ASXL2, RAD21, CSF3R and DNM2 in RUNX1-RUNXT1 leukemia; FLT3, DDX54, WT1 and CALR in PML-RARA promyelocytic leukemia; KIT and BCORL1 in CBFB-rearranged leukemia. In addition, 9% of cases showed rearrangements of KMT2A, with known (e.g. MLLT3) and non-canonical partners (e.g. ACACA, and NCBP1) and poor outcome. Although common targets of mutations have been previously described for myeloid malignancies, the heterogeneity and complexity of mutational patterns, their expression signature and outcome here described are novel. Gene expression analysis identified groups of AML and/or MDS lacking recurrent cytogenetic abnormalities (87%). The spectrum of the most frequently mutated genes (>10 cases) and associated gene expression subtypes is summarized in Figure 1A. TET2 (more frequent in MDS than AML, p=0.0011) and DNMT3A (more frequent in AML than MDS, p<0.0001) were the most frequently mutated genes. Interestingly, mutations in these genes promoting clonal hematopoiesis were significantly enriched in the subgroup with NPM1 mutations. Overall, NPM1 mutations occurred in 27.4% of AML and 1% of MDS and were characterized by four expression signatures with different combination of cooperating mutations in cohesin and signaling genes and outcome (Fig. 1C, gene expression, GE, groups 2, 3, 7 and 8). Co-occurring NPM1 and FLT3 mutations conferred poorer outcome compared to only NPM1, in contrast co-occurring mutations with cohesin genes had better outcome (Fig. 1D). Additional mutations that significantly co-occurred with NPM1 were in PTPN11, IDH1/2, RAD21 and SMC1A. Three gene expression clusters accounted for additional 9% of cases with mutual exclusive mutations in RUNX1,TP53 and CEBPA and co-occurring with a combination of mutations in DNA methylation, splicing and signaling genes (Fig. 1E, GE groups 4, 5 and 6). Interestingly, RUNX1 mutations were significantly associated with SRSF2 mutations but not with SF3B1, showed high expression of MN1 and poor outcome (Fig. 1F). In contrast to the distinct, mutation-associated patterns of gene expression in AML samples, the gene expression profile of MDS was less variable despite diversity in patterns of mutation. MDS was enriched in mutations of SF3B1 (27.2%), mutually exclusive with SFRS2 (14.4%) and U2AF1 (5.5%); TP53 (13.7%) and RUNX1 (10.5%) and a combination of mutations in epigenetic regulators with outcome dependent on mutational pattern (Fig. 1A, G-H). Moreover, structural variations and/or missense mutations of MECOM accounted for 2% of cases. Conclusions: the integration of mutational and expression data from a large cohort of adult pan myeloid leukemia cases enabled the definition of subtypes and constellations of mutations and have prognostic significance that transcends prior gene panel-based classification schema. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Baer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Mullighan:Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Chen, Di, Gaopeng Li, Chunxia Ji, Qiqi Lu, Ying Qi, Chao Tang, Ji Xiong, et al. "TMIC-11. ENHANCED B7-H4 EXPRESSION IN GLIOMAS WITH LOW PD-L1 EXPRESSION IDENTIFIES COLD TUMORS." Neuro-Oncology 21, Supplement_6 (November 2019): vi249. http://dx.doi.org/10.1093/neuonc/noz175.1045.
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Abstract The expression profiles of different immune checkpoint molecules are promising for triaging personalized targeted immunotherapy. Gliomas have been shown as potential targets for immune checkpoint inhibitors. Our study was performed to determine co-expression levels of two major B7 immune molecules PD-L1 and B7-H4 in gliomas in which both have demonstrated to inhibit anti-tumor host immunity. We assessed tumor issues from primary gliomas stage II–IV(n=505) by immunohistochemistry (IHC) for protein levels of both PD-L1 and B7-H4. Gene co-expression analysis assessing clusters based on extent of PD-L1/B7-H4 classifier genes expression were investigated in two transcriptome datasets (TCGA and CGGA) to validate IHC expression profiles. Here, we found that 61% and 54% of patient samples were positive for PD-L1 and B7-H4 respectively, whereby high-expression of either protein was limited to 23% and 20% respectively. Co-expression of PD-L1 and B7-H4 in high levels was limited to 2%. Comparable results were seen in RNA-seq datasets when PD-L1 mRNA expression level corelated negatively with B7-H4. Gene co-expression modules clustered in each grade gliomas without Double-High modules (glioma cluster with high mRNA expression of both PD-L1 and B7-H4 classifier genes) also verified restricted co-expression pattern. B7-H4 mRNA expression level had negative correlation with extent of immune cell infiltration, including tumor-infiltrating lymphocytes (TILs), and High-B7-H4 module gliomas (high B7-H4 but low PD-L1 classifier genes expression) were related to a cold tumor with less TILs. The majority of gliomas express PD-L1 or B7-H4, however, co-expression of both at high levels is minimal. The High-B7-H4 module was significantly lacking in TILs, suggesting that B7-H4 might inhibit T cell trafficking into the central nervous system (CNS). This study demonstrates that PD-L1 expression alone is not fully informative in gliomas for immune targeted or active-specific immunotherapy, and PD-L1 and B7-H4 probably inhibit different aspects of the T cell functions.
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Aggoune, Djamel, Nathalie Sorel, Sanaa El Marsafy, Marie Laure Bonnet, Denis Clay, Marie Claude Meunier, Karin Tarte, et al. "Molecular Characterization of the Leukemic Niche in Chronic Myeloid Leukemia (CML) and Evaluation of a Leukemia / Niche Cross-Talk." Blood 120, no. 21 (November 16, 2012): 908. http://dx.doi.org/10.1182/blood.v120.21.908.908.
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Abstract Abstract 908 There is growing evidence that the bone marrow microenvironment could participate to the progression of chronic myeloid leukemia (CML). Recent data show indeed that placental growth factor (PGF) expression is highly induced in stromal cells from CML patients although they are not part of the leukemic clone as they are Ph1-negative (Schmidt et al, Cancer Cell 2011). It is possible that leukemic cells instruct the niche components via extracellular or contact signals, transforming progressively the “normal niche” into a functionally “abnormal niche” by inducing aberrant gene expression in these cells, similar to the pattern that has been identified in cancer-associated fibroblasts (CAF). In an effort to identify the differential gene expression pattern in the CML niche, we have undertaken two strategies of gene expression profiling using a Taqman Low Density Arrays (TLDA) protocol designed for 93 genes involved in antioxidant pathways (GPX, PRDX, SOD families), stromal cell biology (Collagen, clusterin, FGF, DHH), stem cell self-renewal (Bmi1, MITF, Sox2) and hematopoietic malignancies (c-Kit, hTERT, Dicer, beta-catenin, FOXO3). The first strategy consisted in the analysis of mesenchymal stem cells (MSCs) isolated from the bone marrow of newly diagnosed CP-CML patients (n=11). As a control, we have used MSCs isolated from the bone marrow of age-matched donors (n=3). MSCs were isolated by culturing 6–8.106 bone marrow mononuclear cells in the presence of b-FGF (1 ng/ml). At 2–3 weeks, cells were characterized by the expression of cell surface markers (CD105+, CD90+) and by their potential of differentiation towards osteoblastic, chondrocytic and adipocytic lineages. The second strategy aimed to study the potential instructive influence of leukemic cells in the gene expression program of normal MSC after co-culture with either the UT7 cell line expressing BCR-ABL (3 days) or with CD34+ cells isolated from CP-CML at diagnosis (5 days) as compared to co-culture with cord blood CD34+ cells. After culture, CD45-negative MSC were cell-sorted and analyzed by TLDA. All results were analyzed using the StatMiner software. Results: TLDA analysis of gene expression pattern of MSC from CML patients (n=11) as compared to normal MSCs (n=3) identified 6 genes significantly over-expressed in CML-MSC: PDPN (10-Fold Increase), V-CAM and MITF (∼8 Fold increase), MET, FOXO3 and BMP-1 (∼ 5 Fold increase). To confirm these results we have performed Q-RT-PCR in a cohort of CML-MSC (n= 14, including the 11 patients as analyzed in TLDA) as compared to normal MSC. High levels of PDPN (Podoplanin, ∼8 fold increase), MITF (Microphtalmia Associated Transcription factor, 4-Fold) and VCAM (Vascular Cell Adhesion Protein, 2 fold increase) mRNA were again observed on CML MSCs. Our second strategy (co-culture of normal MSC with BCR-ABL-expressing UT7) revealed an increase of IL-8 and TNFR mRNA expression in co-cultured MSCs (∼5-fold ) whereas there was a major decrease in the expression of DHH (∼ 25-fold) upon contact with BCR-ABL-expressing cells. No modification of the expression of PDPN, MITF or VCAM was noted in normal MSC after this 3-day co-culture strategy using UT7-BCR-ABL cells. Current experiments are underway to determine if primary CD34+ cells from CML patients at diagnosis could induce a specific gene expression pattern in normal MSC after 5 days of co-culture. PDPN is a glycoprotein involved in cell migration and adhesion, acting downstream of SRC. It has been shown to promote tumor formation and progression in solid tumor models and is highly expressed in CAFs. MITF is a bHLH transcription factor involved in the survival of melanocyte stem cells and metastatic melanoma. Finally, high VCAM1 mRNA expression by MSCs from CML patients could be involved in increased angiogenesis known to be present on CML microenvironment. In conclusion, our results demonstrate an abnormal expression pattern of 3 important genes (PDPN, MITF and VCAM1) in MSC isolated in CP-CML patients at diagnosis. The mechanisms leading to an increased mRNA expression (instructive or not instructive by leukemic cells) and their relevance to CML biology are under evaluation. Our results, confirming previous data, suggest strongly the existence of a molecular cross-talk between leukemic cells and the leukemic niche. The elucidation of such aberrant pathways in the microenvironment could lead to the development of “niche-targeted” therapies in CML. Disclosures: Turhan: Novartis, Bristol Myers Squibb: Honoraria, Research Funding.
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Okada, Kazuma, and Chikako Honda. "Molecular Mechanisms Regulating the Columnar Tree Architecture in Apple." Forests 13, no. 7 (July 10, 2022): 1084. http://dx.doi.org/10.3390/f13071084.
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The columnar apple cultivar ‘McIntosh Wijcik’ was discovered as a spontaneous mutant from the top of a ‘McIntosh’ tree in the early 1960s. ‘McIntosh Wijcik’ exhibits the columnar growth phenotype: compact and sturdy growth, short internodes, and very few lateral shoots. Classical genetic analysis revealed that the columnar growth phenotype of ‘McIntosh Wijcik’ is controlled by a single dominant gene, Co. This review focuses on the advances made toward understanding the molecular mechanisms of columnar growth in the last decade. Molecular studies have shown that an 8.2 kb insertion in the intergenic region of the Co locus is responsible for the columnar growth phenotype of ‘McIntosh Wijcik’, implying that the insertion affects the expression patterns of adjacent genes. Among the candidate genes in the Co region, the expression pattern of MdDOX-Co, putatively encoding 2-oxoglutarate-dependent dioxygenase (DOX), was found to vary between columnar and non-columnar apples. Recent studies have found three functions of MdDOX-Co: facilitating bioactive gibberellin deficiency, increasing strigolactone levels, and positively regulating abscisic acid levels. Consequently, changes in these plant hormone levels caused by the ectopic expression of MdDOX-Co in the aerial organs of ‘McIntosh Wijcik’ can lead to dwarf trees with fewer lateral branches. These findings will contribute to the breeding and cultivation of new columnar apple cultivars with improved fruit quality.
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Samaniego, Felipe, Lalit Sehgal, Frank K. Braun, Zuzana Berkova, Jorge E. Romaguera, Michael Wang, M. Alma Rodriguez, Sattva S. Neelapu, and Rohit Mathur. "Molecular Signatures of Tumor-Initiating Cells Unveil Wnt Pathway As a Therapeutic Target in Mantle Cell Lymphoma." Blood 124, no. 21 (December 6, 2014): 2148. http://dx.doi.org/10.1182/blood.v124.21.2148.2148.
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Abstract Introduction Mantle cell lymphoma (MCL) is an aggressive and incurable form of non-Hodgkin’s lymphoma. Despite initial responses to intense chemotherapy, up to 50% of cases of MCL relapse, often in a chemoresistant form. We hypothesized that the recently identified MCL-initiating cells (MCL-ICs) are the main reason for relapse and chemoresistance of MCL. Methods We isolated MCL-ICs from primary MCL cells on the basis of a defined marker expression pattern; CD34-CD3-CD45+CD19-. The MCL-ICs, MCL-non-ICs, and peripheral blood lymphocytes from healthy donors were analyzed for gene expression using the Arraystar platform. The differences in mRNA levels of genes of interest were confirmed by quantitative RT-PCR. The prominent differentially expressed transcripts were analyzed using the Ingenuity Platform. Primary MCL cells were co-culture with mesenchymal stem cells to assess the effects of chemotherapeutic agents such as vincristine, doxorubicin and the newly approved Burton tyrosine kinase inhibitor ibrutinib, and Wnt signaling inhibitors. Results Approximately 1% of primary MCL cells are MCL-ICs and they can be maintained in co-culture with mesenchymal stem cells. Comparison of gene expression profiles of MCL-ICs and MCL-non-ICs revealed activation of stem cell-specific pathways in MCL-ICs by expression of Wnt, Notch, and Hedgehog and enhanced expression of Nanog, Oct4, KLF4, ADH1, MT1b and ABCC3. Gene expression microarray data and RT-PCR data suggested predominant activation of the Wnt/Frizzled pathway. Indeed, MCL-ICs were particularly sensitive to Wnt pathway inhibitors. Targeting Wnt-dependent β-catenin‒TCF4 interaction with CCT036477, iCRT14, or PKF118-310 preferentially eliminated the MCL-ICs, reduced the expression of stem cell transcription factors (Myc, Nanog, Oct4, Klf4), and sensitized MCL cells to vincristine, doxorubicin, and ibrutinib. Interestingly, while vincristine, doxorubicin or ibrutinib did kill MCL cells, they did not reduce the percentage of MCL-ICs in treated co-culture. Conclusion MCL-ICs are present in primary MCL isolates and they show gene expression pattern of chemoresistant, stem cell-like cells with predominant activation of Wnt signaling. In order to produce durable remissions in MCL patients, treatment strategies should be directed to target MCL-ICs. Disclosures Wang: Pharmacyclics, Janssen: Honoraria, Research Funding.
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Zaman, Fatima, Meng Zhang, Ying Liu, Zhilin Wang, Liqing Xu, Dayong Guo, Zhengrong Luo, and Qinglin Zhang. "DkmiR397 Regulates Proanthocyanidin Biosynthesis via Negative Modulating DkLAC2 in Chinese PCNA Persimmon." International Journal of Molecular Sciences 23, no. 6 (March 16, 2022): 3200. http://dx.doi.org/10.3390/ijms23063200.
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Persimmon fruits accumulate a large amount of proanthocyanidins (PAs), which makes an astringent sensation. Proanthocyanidins (PAs) are the polymers of flavan-3-ols stored in plant vacuoles under laccase activation. A laccase gene, DkLAC2, is putatively involved in PAs biosynthesis and regulated by microRNA (DkmiR397) in persimmon. However, the polymerization of PAs in association with miRNA397 still needs to be explored in persimmon. Here, we identified pre-DkmiR397 and its target gene DkLAC2 in ‘Eshi 1’ persimmon. Histochemical staining with GUS and dual luciferase assay both confirmed DkmiR397-DkLAC2 binding after co-transformation in tobacco leaves. Diverse expression patterns of DkLAC2 and DkmiR397 were exhibited during persimmon fruit development stages. Moreover, a contrasting expression pattern was also observed after the combined DkLAC2-miR397 transformation in persimmon leaves, suggesting that DkmiR397 might be a negative regulator of DkLAC2. Similarly, the transient transformation of DkmiR397 in persimmon fruit discs in vitro also reduced PA accumulation by repressing DkLAC2, whereas the up-regulation of DkLAC2 increased the accumulation of PAs by short tandem target mimic STTM-miR397. A similar expression pattern was observed when overexpressing of DkLAC2 in Arabidopsis wild type (WT) and overexpression of DkLAC2, DkmiR397 in persimmon leaf callus. Our results revealed that the role of DkmiR397 repressed the expression of DkLAC2 concerning PA biosynthesis, providing a potential target for the manipulation of PAs metabolism in persimmon.
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Wu, Tianyi, Shanhe Wang, Qiunan Jin, Xiaoyang Lv, and Wei Sun. "PAPPA2 Promote the Proliferation of Dermal Papilla Cells in Hu Sheep (Ovis aries) by Regulating IGFBP5." Genes 12, no. 10 (September 24, 2021): 1490. http://dx.doi.org/10.3390/genes12101490.
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Hu sheep (Ovis aries) is a rare white sheep breed, with four different types of lambskin patterns that have different values. However, the genetic mechanisms underlying different types of pattern formation remains unclear. This research aimed to characterize the molecular mechanism of differentially expressed gene PAPPA2 affecting the pattern type of Hu sheep’s lambskin at the cellular level. Thus, RT-qPCR, EdU and Cell Cycle detection were used to explore the effect of PAPPA2 and IGFBP5 (a protein that can be hydrolyzed by PAPPA2) on the proliferation of dermal papilla cells (DPCs) after overexpression or interference with PAPPA2 and IGFBP5. The expression level of PAPPA2 in straight DPCs was 4.79 ± 1.84 times higher than curved. Overexpression of PAPPA2 promoted the proliferation of DPCs and also increased the expression of IGFBP5. Conversely, overexpression of IGFBP5 reduced the proliferation of DPCs. However, the proliferation of DPCs was restored by co-overexpression of PAPPA2 and IGFBP5 compared with overexpression of IGFBP5 alone. Thus, PAPPA2 can affect the proliferation of DPCs through regulating IGFBP5 and then participate in lambskin pattern determination. Overall, we preliminarily clarified the critical role played by PAPPA2 during the formation of different pattern in Hu sheep lambskin.
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Scripture-Adams, Deirdre, Constantin Georgescu, and Ellen Rothenberg. "Transcription factor expression pattern differences are present in OP9 culture derived fetal liver origin early thymocytes when compared to fetal and adult thymocytes (64.22)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 64.22. http://dx.doi.org/10.4049/jimmunol.186.supp.64.22.
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Abstract The advent of the OP9 stromal culture system has tremendously improved our ability to replicate T cell development in vitro. While giving unprecedented access and numerical advantage, these cells may not mirror real thymocytes in their developmental capacity and transcription factor expression patterns. We have examined the pattern of expression of 65 developmentally regulated gene transcripts across the early thymocyte stages of DN1, DN2, DN3 and DN4, in fetal liver derived thymocytes (FLDN) derived from co-culture on OP9 DL-1 cells, and compared them to those found in fetal and adult thymocytes using real time quantitative PCR. Our assessment suggests an overall pattern of similarity between FLDN expression patterns and “real” freshly isolated thymocytes, but some classes of genes are not regulated similarly, and these may have important consequences for development and progression. We present a cluster analysis identifying transcription factors which are differentially regulated in FLDN relative to adult and fetal populations, and identify groups of factors which track with those differentially regulated transcripts. We additionally analyze the effect of long vs. short term culture on these changes in the transcription factor control network that drives T cell development.
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KAKINUMA, Yoshihiko, Takashi MIYAUCHI, Takahiko SUZUKI, Koichi YUKI, Nobuyuki MURAKOSHI, Katsutoshi GOTO, and Iwao YAMAGUCHI. "Enhancement of glycolysis in cardiomyocytes elevates endothelin-1 expression through the transcriptional factor hypoxia-inducible factor-1 α." Clinical Science 103, s2002 (September 1, 2002): 210S—214S. http://dx.doi.org/10.1042/cs103s210s.
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We investigated whether the type of energy metabolism directly affects cardiac gene expression. During development, the heart switches from glycolysis to fatty acid β-oxidation in vivo, as demonstrated by the developmental switching of the major isoform of myosin heavy chain (MHC) from β to α. However, the β-MHC isoform predominates in monocrotaline-induced pulmonary hypertension, a model of right ventricular hypertrophy in vivo. Cultured cardiomyocytes showed a predominance of β-MHC expression over that of α-MHC, the same pattern as in the hypertrophied heart, suggesting that the in vitro condition itself causes the energy metabolism of cardiomyocytes to be switched to glycolysis. Electrical stimulation of cultured cardiomyocytes decreased the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and hypoxia-inducible factor-1α (HIF-1α), but not that of peroxisome-proliferator-activated receptor-γ co-activator, suggesting that electrical stimulation suppresses the glycolytic system. Furthermore, a higher oxygen content (50%) decreased drastically the expression of GAPDH, HIF-1α and endothelin-1 (ET-1), and increased [3H]palmitate uptake. These findings indicate that the intrinsic energy metabolic system in cultured cardiomyocytes in vitro is predominantly glycolysis, and that the gene expression of cardiac ET-1 parallels the state of the glycolytic system. An antisense oligonucleotide against HIF-1α greatly decreased the gene expression of ET-1 and GAPDH, suggesting that cardiac ET-1 gene expression is regulated by cardiac energy metabolism through HIF-1α. In conclusion, it is suggested that the pattern of gene expression of ET-1 reflects the level of the glycolytic system in cardiomyocytes, and that enhanced glycolysis regulates the cardiac gene expression of ET-1 via HIF-1α.
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Figueiredo, Filipe, Harald Kristoffersen, Shripathi Bhat, Zuobing Zhang, Jacques Godfroid, Stefano Peruzzi, Kim Præbel, Roy Ambli Dalmo, and Xiaoli Xu. "Immunostimulant Bathing Influences the Expression of Immune- and Metabolic-Related Genes in Atlantic Salmon Alevins." Biology 10, no. 10 (September 29, 2021): 980. http://dx.doi.org/10.3390/biology10100980.
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Disease resistance of fish larvae may be improved by bath treatment in water containing immunostimulants. Pattern recognition receptors, such as TLR3, TLR7, and MDA5, work as an “early warning” to induce intracellular signaling and facilitate an antiviral response. A single bath of newly hatched larvae, with Astragalus, upregulated the expression of IFNα, IFNc, ISG15, MDA5, PKR, STAT1, TLR3, and TLR7 immune genes, on day 4 post treatment. Similar patterns were observed for Hyaluronic acid and Poly I:C. Increased expression was observed for ISG15, MDA5, MX, STAT1, TLR3, TLR7, and RSAD2, on day 9 for Imiquimod. Metabolic gene expression was stimulated on day 1 after immunostimulant bath in ULK1, MYC, SLC2A1, HIF1A, MTOR, and SIX1, in Astragalus, Hyaluronic acid, and Imiquimod. Expression of NOS2 in Poly I:C was an average fourfold above that of control at the same timepoint. Throughout the remaining sampling days (2, 4, 9, 16, 32, and 45 days post immunostimulant bath), NOS2 and IL1B were consistently overexpressed. In conclusion, the immunostimulants induced antiviral gene responses, indicating that a single bath at an early life stage could enable a more robust antiviral defense in fish. Additionally, it was demonstrated, based on gene expression data, that cell metabolism was perturbed, where several metabolic genes were co-regulated with innate antiviral genes.
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Chen, Tianchi, Tao Xu, Tianye Zhang, Tingting Liu, Leyi Shen, Zhihui Chen, Yueyan Wu, and Jian Yang. "Genome-Wide Identification and Characterization of DnaJ Gene Family in Grape (Vitis vinifera L.)." Horticulturae 7, no. 12 (December 18, 2021): 589. http://dx.doi.org/10.3390/horticulturae7120589.
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Grape production in southern China suffers great loss due to various environmental stresses. To understand the mechanism of how the grape plants respond to these stresses is an active area of research in developing cultivation techniques. Plant stress resistance is known to rely on special proteins. Amongst them, DnaJ protein (HSP40) serves as co-chaperones of HSP70, playing crucial roles in various stress response. However, the DnaJ proteins encoded by the DnaJ gene family in Vitis vinifera L. have not been fully described yet. In this study, we identified 78 VvDnaJs in the grape genome that can be classified into three groups—namely, DJA, DJB, and DJC. To reveal the evolutionary and stress response mechanisms for the VvDnaJ gene family, their evolutionary and expression patterns were analyzed using the bioinformatic approach and qRT-PCR. We found that the members in the same group exhibited a similar gene structure and protein domain organization. Gene duplication analysis demonstrated that segmental and tandem duplication may not be the dominant pathway of gene expansion in the VvDnaJ gene family. Codon usage pattern analysis showed that the codon usage pattern of VvDnaJs differs obviously from the monocotyledon counterparts. Tissue-specific analysis revealed that 12 VvDnaJs present a distinct expression profile, implying their distinct roles in various tissues. Cis-acting element analysis showed that almost all VvDnaJs contained the elements responsive to either hormones or stresses. Therefore, the expression levels of VvDnaJs subjected to exogenous hormone applications and stress treatments were determined, and we found that VvDnaJs were sensitive to hormone treatments and shade, salt, and heat stresses, especially VIT_00s0324g00040. The findings of this study could provide comprehensive information for the further investigation on the genetics and protein functions of the DnaJ gene family in grape.
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Zhao, Ziru, Xiao Hu, Zhourui Wu, Qi Chen, and Qihui Shao. "A Selective P2Y Purinergic Receptor Agonist 2-MesADP Enhances Locomotor Recovery after Acute Spinal Cord Injury." European Neurology 83, no. 2 (2020): 195–212. http://dx.doi.org/10.1159/000507854.
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Introduction: Spinal cord injury (SCI) causes most severe motor and sensory dysfunctions. In Chinese traditional medicine, the agonist of a purinergic receptor is believed to have a positive effect on SCIs, and 2-Methylthio-adenosine-5′-diphosphate (2-MesADP) is a selective agonist of the P2Y purinergic receptor. Methods: To investigate its therapeutic function and molecular mechanism in SCI, transcriptome analysis associated with weighted gene co-expression network analysis (WGCNA) was carried out at various time points after T9 crush injury. Results: 2-MesADP demonstrated recovery of limb motor function at the 6 weeks after injury, accompanied by neuronal regeneration and axon remyelination at 2 and 6 weeks. Furthermore, gene profiling revealed alternated gene expression with the treatment of 2-MesADP. These genes were assigned to a total of 38 modules, followed by gene ontology analysis; of these, 18 represented neuronal apoptosis and regeneration, immune response, synaptic transmission, cell cycle, and angiogenesis. In the neuronal apoptosis and regeneration module, Nefh, NeuroD6, and Dcx in the 2-MesADP group were noticed due to their interesting expression pattern. The gene expression patterns of Mag, Mog, and Cnp, which played key roles in myelination, were significantly changed with the treatment of 2-MesADP. Wnt signal pathway was the most important pathway in 2-MesADP treatment for acute SCI. Conclusion: 2-MesADP enhanced locomotor recovery in mouse SCI by altering the expression of neuronal apoptosis and remyelination-related genes and Wnt signaling pathways.
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Stanford, Felicia Adelina, Nina Matthies, Zoltán Cseresnyés, Marc Thilo Figge, Mohamed I. Abdelwahab Hassan, and Kerstin Voigt. "Expression Patterns in Reductive Iron Assimilation and Functional Consequences during Phagocytosis of Lichtheimia corymbifera, an Emerging Cause of Mucormycosis." Journal of Fungi 7, no. 4 (April 3, 2021): 272. http://dx.doi.org/10.3390/jof7040272.
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Iron is an essential micronutrient for most organisms and fungi are no exception. Iron uptake by fungi is facilitated by receptor-mediated internalization of siderophores, heme and reductive iron assimilation (RIA). The RIA employs three protein groups: (i) the ferric reductases (Fre5 proteins), (ii) the multicopper ferroxidases (Fet3) and (iii) the high-affinity iron permeases (Ftr1). Phenotyping under different iron concentrations revealed detrimental effects on spore swelling and hyphal formation under iron depletion, but yeast-like morphology under iron excess. Since access to iron is limited during pathogenesis, pathogens are placed under stress due to nutrient limitations. To combat this, gene duplication and differential gene expression of key iron uptake genes are utilized to acquire iron against the deleterious effects of iron depletion. In the genome of the human pathogenic fungus L. corymbifera, three, four and three copies were identified for FRE5, FTR1 and FET3 genes, respectively. As in other fungi, FET3 and FTR1 are syntenic and co-expressed in L. corymbifera. Expression of FRE5, FTR1 and FET3 genes is highly up-regulated during iron limitation (Fe-), but lower during iron excess (Fe+). Fe- dependent upregulation of gene expression takes place in LcFRE5 II and III, LcFTR1 I and II, as well as LcFET3 I and II suggesting a functional role in pathogenesis. The syntenic LcFTR1 I–LcFET3 I gene pair is co-expressed during germination, whereas LcFTR1 II- LcFET3 II is co-expressed during hyphal proliferation. LcFTR1 I, II and IV were overexpressed in Saccharomyces cerevisiae to represent high and moderate expression of intracellular transport of Fe3+, respectively. Challenge of macrophages with the yeast mutants revealed no obvious role for LcFTR1 I, but possible functions of LcFTR1 II and IVs in recognition by macrophages. RIA expression pattern was used for a new model of interaction between L. corymbifera and macrophages.
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Konda, Aravind K., Parasappa R. Sabale, Khela R. Soren, Shanmugavadivel P. Subramaniam, Pallavi Singh, Santosh Rathod, Sushil K. Chaturvedi, and Narendra P. Singh. "Systems Biology Approaches Reveal a Multi-stress Responsive WRKY Transcription Factor and Stress Associated Gene Co-expression Networks in Chickpea." Current Bioinformatics 14, no. 7 (September 17, 2019): 591–601. http://dx.doi.org/10.2174/1574893614666190204152500.
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Background: Chickpea is a nutritional rich premier pulse crop but its production encounters setbacks due to various stresses and understanding of molecular mechanisms can be ascribed foremost importance. Objective: The investigation was carried out to identify the differentially expressed WRKY TFs in chickpea in response to herbicide stress and decipher their interacting partners. Methods: For this purpose, transcriptome wide identification of WRKY TFs in chickpea was done. Behavior of the differentially expressed TFs was compared between other stress conditions. Orthology based cofunctional gene networks were derived from Arabidopsis. Gene ontology and functional enrichment analysis was performed using Blast2GO and STRING software. Gene Coexpression Network (GCN) was constructed in chickpea using publicly available transcriptome data. Expression pattern of the identified gene network was studied in chickpea-Fusarium interactions. Results: A unique WRKY TF (Ca_08086) was found to be significantly (q value = 0.02) upregulated not only under herbicide stress but also in other stresses. Co-functional network of 14 genes, namely Ca_08086, Ca_19657, Ca_01317, Ca_20172, Ca_12226, Ca_15326, Ca_04218, Ca_07256, Ca_14620, Ca_12474, Ca_11595, Ca_15291, Ca_11762 and Ca_03543 were identified. GCN revealed 95 hub genes based on the significant probability scores. Functional annotation indicated role in callose deposition and response to chitin. Interestingly, contrasting expression pattern of the 14 network genes was observed in wilt resistant and susceptible chickpea genotypes, infected with Fusarium. Conclusion: This is the first report of identification of a multi-stress responsive WRKY TF and its associated GCN in chickpea.
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Galai, Geut, Hila Ben-David, Liron Levin, Martin F. Orth, Thomas G. P. Grünewald, Shai Pilosof, Shimon Bershtein, and Barak Rotblat. "Pan-Cancer Analysis of Mitochondria Chaperone-Client Co-Expression Reveals Chaperone Functional Partitioning." Cancers 12, no. 4 (March 30, 2020): 825. http://dx.doi.org/10.3390/cancers12040825.
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Metabolic reprogramming is a hallmark of cancer. Such reprogramming entails the up-regulation of the expression of specific mitochondrial proteins, thus increasing the burden on the mitochondrial protein quality control. However, very little is known about the specificity of interactions between mitochondrial chaperones and their clients, or to what extent the mitochondrial chaperone–client co-expression is coordinated. We hypothesized that a physical interaction between a chaperone and its client in mitochondria ought to be manifested in the co-expression pattern of both transcripts. Using The Cancer Genome Atlas (TCGA) gene expression data from 13 tumor entities, we constructed the mitochondrial chaperone-client co-expression network. We determined that the network is comprised of three distinct modules, each populated with unique chaperone-clients co-expression pairs belonging to distinct functional groups. Surprisingly, chaperonins HSPD1 and HSPE1, which are known to comprise a functional complex, each occupied a different module: HSPD1 co-expressed with tricarboxylic acid cycle cycle enzymes, while HSPE1 co-expressed with proteins involved in oxidative phosphorylation. Importantly, we found that the genes in each module were enriched for discrete transcription factor binding sites, suggesting the mechanism for the coordinated co-expression. We propose that our mitochondrial chaperone–client interactome can facilitate the identification of chaperones supporting specific mitochondrial pathways and bring forth a fundamental principle in metabolic adaptation.
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Dahse, Regine, and Hartwig Kosmehl. "CELL SEPARATION AND GENE EXPRESSION ANALYSIS IN A TUMOR-STROMA INTERACTION MODEL." Image Analysis & Stereology 23, no. 3 (May 3, 2011): 153. http://dx.doi.org/10.5566/ias.v23.p153-157.
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A novel technique for co-culturing and separating fibroblasts and carcinoma cells in a 2-D model of tumorstroma interaction is presented. The methodology is based on cell co-cultivation on an 1.35 μm thin membrane followed by rapid immunostaining and microdissection of the different cell compartments using a laser microdissection system (P.A.L.M. Microlaser Technologies AG, Germany). For identifying the tumor cell compartment, immunolabeling for a marker that is expressed only in epithelial tumor cells is performed. The RNA quality from the microdissected co-cultured cells was successfully proved by RT-PCR for a housekeeping gene transcript and for the laminin gamma 2 chain gene transcript used before in the tumor cell immunostaining. Laminin cDNA was amplificable only in tumor cells and not in the co-cultivated fibroblasts indicating no cell-cross-contamination during microdissection. Microdissected tumor and stroma cells from the presented membrane based co-culture model can be used for gene expression profiling and DNA based analysis in the investigation of tumor-stroma interactions.
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Knaus, Hanna A., Sofia Berglund, Hubert Hackl, Raúl Montiel-Esparza, Mark J. Levis, Judith E. Karp, Ivana Gojo, and Leo Luznik. "Acute Myeloid Leukemia (AML) Blasts Influence the Gene Expression Signature and Co-Signaling Receptor Expression of CD8+ T Cells." Blood 128, no. 22 (December 2, 2016): 1700. http://dx.doi.org/10.1182/blood.v128.22.1700.1700.
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Abstract Background: T cell dysfunction in AML remains poorly understood. Our previous studies of AML-associated T cell dysfunction (Knaus, ASH 2015) have focused on expression of multiple inhibitory receptors by T cells in AML patients. Transcriptional signatures, however, remain relatively unexplored, as does the role of Blast/T cell interactions on T cell function. Deciphering those could be crucial for integration of future immunotherapies into clinical practice. Therefore, we aimed to characterize CD8+ T cell gene expression signatures in newly diagnosed AML patients before and after treatment, and to decipher the effects of AML blasts on the expression of co-signaling molecules by CD8+ T cells in co-culture experiments. Methods: Serial peripheral blood (PB) samples (at diagnosis and at the recovery after induction chemotherapy) were collected. To study transcriptional signatures, RNA isolated from FACS-purified PB CD8+ T cells from 6 patients [3 responders (R) and 3 non-responders (NR)] and 4 healthy controls (HC) was analyzed with the Human Prime View Gene Expression Array (Affymetrix). The data were normalized and log transformed. Expression fold change (FC), p values and false discovery rate were determined. Enrichment of canonical pathways was determined using Ingenuity Pathway Analysis (IPA, QIAGEN). To study AML blast-T cell interactions, we FACS-purified T cells and primary AML blasts at diagnosis (n=13) and T cells from HC (n=12). T cells were cultured in vitro for 3 days in the presence or absence of blasts (T cell:blast ratio 1:10) and analyzed by flow cytometry. Results: The transcriptional profile of CD8+ T cells at AML diagnosis significantly differed from that of HC. Genes were selected based on >2 FC between patient and HC, and p< 0.01. We identified a total of 453 dysregulated genes, of which 237 were up- and 216 down-regulated. Upregulated genes included immune inhibitory receptors LILRB1, 2B4, KLRG1, CD160, the transcription factors EOMES, TBET, TIGIT and cytokines (granzyme-A/B/K). In contrast, co-stimulatory receptor genes were downregulated, including CD40LG, CD28, CD30LG and CD28H. Canonical pathways analysis with IPA revealed that the NFAT pathway (involved in T cell differentiation and self-tolerance) was highly upregulated, while co-stimulatory CD28, ICOS and OX40 signaling pathways were downregulated in CD8+ T cells at AML diagnosis. Next, we compared R to NR after induction chemotherapy. There were a total of 351 dysregulated genes; 108/243 genes were up-/down-regulated, respectively. R patients upregulated immune stimulatory receptor genes like ICOS, whereas the top expressed genes for NR patients included the co-inhibitory receptor TIM3; several members of the inhibitory LIR receptor family; LST1 (involved in inhibition of lymphocyte proliferation); TWEAK-APRIL (associated with T cell apoptosis); and CD39 (terminally exhausted CD8+ T cells). In line with these findings, IPA showed that the co-stimulatory ICOS and OX40 signaling pathways were enriched in R patients. In contrast, the NFAT pathway, which had been highly upregulated at diagnosis, remained enriched in NR, but not in R patients. Results were confirmed by qPCR. The culture assay showed that the presence of primary AML blasts significantly reduced the viability of both AML and HC T cells (p <0.005 in both cases). The presence of AML blasts also significantly decreased the frequency of primary AML T cells expressing co-stimulatory receptors 41BB, ICOS and OX40, while it increased the frequency of HC T cells expressing co-inhibitory receptor 2B4 and the senescence/exhaustion marker CD57 compared to their counterparts cultured without blasts. Conclusions: Our study provides insight into the genomic CD8+ T cell signatures of AML patients at diagnosis and following chemotherapy. At diagnosis, T cells overexpressed genes that negatively regulate T cell immune responses, while genes that positively regulate immune responses were downregulated. Interestingly, after induction chemotherapy these changes persisted in NR only. Additionally, a pattern of decreased viability and co-stimulatory receptor expression was seen after in vitro co-culture of T cells with AML blasts, whereas immune inhibitory receptor expression was increased. Our data suggests that the blasts themselves influence the T cell phenotype and genotype in AML patients and that remission is associated with reversion to HC pattern. Disclosures Levis: Astellas: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Millennium: Consultancy, Research Funding.
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Konsavage, Wesley M., Sydney L. Kyler, Sherri A. Rennoll, Ge Jin, and Gregory S. Yochum. "Wnt/β-Catenin Signaling Regulates Yes-associated Protein (YAP) Gene Expression in Colorectal Carcinoma Cells." Journal of Biological Chemistry 287, no. 15 (February 15, 2012): 11730–39. http://dx.doi.org/10.1074/jbc.m111.327767.
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Mutations in the Wnt/β-catenin pathway occur in most colorectal cancers (CRCs), and these mutations lead to increased nuclear accumulation of the β-catenin transcriptional co-activator. In the nucleus, β-catenin associates with TCF/LEF sequence specific transcription factors to activate target gene expression. The Hippo pathway restricts cellular growth by preventing nuclear accumulation of the Yes-associated protein (YAP) transcriptional co-activator. YAP expression is elevated in CRCs suggesting that, like Wnt/β-catenin signaling, the Hippo pathway may contribute to colorectal carcinogenesis. Regulation of YAP at the post-translational level has been well studied but the transcription factors that control YAP gene expression are unknown. Here we demonstrate that β-catenin/TCF4 complexes bind a DNA enhancer element within the first intron of the YAP gene to drive YAP expression in CRC cells. As such, reducing β-catenin expression in CRC cells using shRNAs leads to decreased YAP mRNA and protein levels. YAP is abundantly expressed in the cytoplasm and nuclei of several established human colon cancer cell lines and this localization pattern is insensitive to plating density. Finally, we show that YAP expression is elevated in the majority of a panel of primary human colorectal tumors compared with its expression in uninvolved colonic mucosa, and that YAP and β-catenin localize to the nuclear compartment of tumor cells. Together, these results implicate YAP as an oncogene whose expression is driven by aberrant Wnt/β-catenin signaling in human CRC cells.
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Wai, Antt Htet, Md Mustafizur Rahman, Muhammad Waseem, Lae-Hyeon Cho, Aung Htay Naing, Jong-Seong Jeon, Do-jin Lee, Chang-Kil Kim, and Mi-Young Chung. "Comprehensive Genome-Wide Analysis and Expression Pattern Profiling of PLATZ Gene Family Members in Solanum Lycopersicum L. under Multiple Abiotic Stresses." Plants 11, no. 22 (November 15, 2022): 3112. http://dx.doi.org/10.3390/plants11223112.
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PLATZ (plant AT-rich sequence and zinc-binding) family proteins with two conserved zinc-dependent DNA-binding motifs are transcription factors specific to the plant kingdom. The functions of PLATZ proteins in growth, development, and adaptation to multiple abiotic stresses have been investigated in various plant species, but their role in tomato has not been explored yet. In the present work, 20 non-redundant Solanum lycopersicum PLATZ (SlPLATZ) genes with three segmentally duplicated gene pairs and four tandemly duplicated gene pairs were identified on eight tomato chromosomes. The comparative modeling and gene ontology (GO) annotations of tomato PLATZ proteins indicated their probable roles in defense response, transcriptional regulation, and protein metabolic processes as well as their binding affinity for various ligands, including nucleic acids, peptides, and zinc. SlPLATZ10 and SlPLATZ17 were only expressed in 1 cm fruits and flowers, respectively, indicating their preferential involvement in the development of these organs. The expression of SlPLATZ1, SlPLATZ12, and SlPLATZ19 was up- or down-regulated following exposure to various abiotic stresses, whereas that of SlPLATZ11 was induced under temperature stresses (i.e., cold and heat stress), revealing their probable function in the abiotic stress tolerance of tomato. Weighted gene co-expression network analysis corroborated the aforementioned findings by spotlighting the co-expression of several stress-associated genes with SlPLATZ genes. Confocal fluorescence microscopy revealed the localization of SlPLATZ–GFP fusion proteins in the nucleus, hinting at their functions as transcription factors. These findings provide a foundation for a better understanding of the structure and function of PLATZ genes and should assist in the selection of potential candidate genes involved in the development and abiotic stress adaptation in tomato.
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Bo, Dongdong, Xunping Jiang, Guiqiong Liu, Ruixue Hu, and Yuqing Chong. "RNA-Seq Implies Divergent Regulation Patterns of LincRNA on Spermatogenesis and Testis Growth in Goats." Animals 11, no. 3 (February 26, 2021): 625. http://dx.doi.org/10.3390/ani11030625.
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Long intergenic non-coding RNAs (lincRNAs) regulate testicular development by acting on protein-coding genes. However, little is known about whether lincRNAs and protein-coding genes exhibit the same expression pattern in the same phase of postnatal testicular development in goats. Therefore, this study aimed to demonstrate the expression patterns and roles of lincRNAs during the postnatal development of the goat testis. Herein, the testes of Yiling goats with average ages of 0, 30, 60, 90, 120, 150, and 180 days postnatal (DP) were used for RNA-seq. In total, 20,269 lincRNAs were identified, including 16,931 novel lincRNAs. We identified seven time-specifically diverse lincRNA modules and six mRNA modules by weighted gene co-expression network analysis (WGCNA). Interestingly, the down-regulation of growth-related lincRNAs was nearly one month earlier than the up-regulation of spermatogenesis-related lincRNAs, while the down-regulation of growth-related protein-coding genes and the correspondent up-regulation of spermatogenesis-related protein-coding genes occurred at the same age. Then, potential lincRNA target genes were predicted. Moreover, the co-expression network of lincRNAs demonstrated that ENSCHIT00000000777, ENSCHIT00000002069, and ENSCHIT00000005076 were the key lincRNAs in the process of testis development. Our study discovered the divergent regulation patterns of lincRNA on spermatogenesis and testis growth, providing a fresh insight into age-biased changes in lincRNA expression in the goat testis.
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Nielsen, Steen, Søren Mellemkjær, Lars M. Rasmussen, Thomas Ledet, Jens Astrup, Jørgen Weeke, and Jens O. L. Jørgensen. "Gene Transcription of Receptors for Growth Hormone-Releasing Peptide and Somatostatin in Human Pituitary Adenomas1." Journal of Clinical Endocrinology & Metabolism 83, no. 8 (August 1, 1998): 2997–3000. http://dx.doi.org/10.1210/jcem.83.8.5046.
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abstract Growth hormone (GH)-releasing peptides (GHRP) or secretagogs (GHS) constitute a family of synthetic compounds with potent and specific GH releasing activity. The receptor (GHS-R) has recently been cloned even though the endogenous ligand remains to be identified. GHRPs act both at the hypothalamic and the pituitary level through mechanisms involving amplification of GH-releasing hormone activity and functional somatostatin antagonism. In the present study we examined the co-expression of messenger RNA (mRNA) for GHS-R and all 5 somatostatin receptor subtypes (sstr 1–5) in 28 human pituitary tumors by RT-PCR. GHS-R transcription was detected in 11 out of 12 somatotroph adenomas and in 2 out of 2 prolactinomas, whereas GHS-R expression was detected in only 2 out of 14 clinically nonfunctioning adenomas (NFPA), and no expression was seen in the only ACTH secreting adenoma. Almost all tumors expressed sstr 2 mRNA (n = 24), whereas only 1 tumor expressed sstr 4 mRNA. The expression of sstr 3 mRNA was inversely associated with GHS-R expression (P < 0.001), which could be attributed to a high prevalence of sstr 3 expression in NFPA. This study suggests that GHS-R expression is predominantly observed in somatotroph adenomas and much less so in NFPA. Moreover, the presence of a distinct pattern of somatostatin receptor subtype co-expression is suggested, which may provide a molecular basis for the complex interaction between GHRPs and somatostatin.
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Wang, Xue, Qiyan Zhang, Ming Gao, Liwen Wu, Yangdong Wang, and Yicun Chen. "Expression Patterns of MYB (V-myb Myeloblastosis Viral Oncogene Homolog) Gene Family in Resistant and Susceptible Tung Trees Responding to Fusarium Wilt Disease." Forests 10, no. 2 (February 21, 2019): 193. http://dx.doi.org/10.3390/f10020193.
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Vernicia fordii (tung oil tree) is famous in the world for its production of tung oil. Unfortunately, it was infected by the soil-borne fungus Fusarium oxysporum f. sp. fordii 1 (Fof-1) and suffered serious wilt disease. Conversely, its sister species V. montana is highly resistant to Fof-1. The MYB (v-myb myeloblastosis viral oncogene homolog) transcription factors were activated during the pathogen Fof-1 infection according to our previous comparative transcriptomic results. Depending on whether the sequence has a complete MYB-DNA-binding domain, a total of 75 VfMYB and 77 VmMYB genes were identified in susceptible V. fordii and resistant V. montana, respectively. In addition, we detected 49 pairs of one-to-one orthologous Vf/VmMYB genes with the reciprocal-best BLAST-hits (RBH)method. In order to investigate the expression modes and the internal network of MYB transcription factors in the two species responding to Fusarium wilt disease, the expressions of Vf/VmMYBs were then investigated and we found that most orthologous Vf/VmMYB genes exhibited similar expression patterns during the Fof-1 infection. However, four pairs of Vf/VmMYB genes, annotated as unknown proteins and mediator of root architecture, demonstrated absolute opposite expression patterns in the two Vernicia species responding to Fof-1. The interaction network of VmMYB genes were further constructed using weighted gene co-expression network analysis (WGCNA) method and four hub genes showing extremely high interaction with the other 1157 genes were identified. RT-qPCR result verified the opposite expression pattern of the hub gene VmMYB011 and VmMYB041 in two Vernicia species. In summary, co-expression network of the Vf/VmMYBs and significantly opposite related pairs of genes in resistant and susceptible Vernicia species provided knowledge for understanding the molecular basis of Vernicia responding to Fusarium wilt disease.