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1
Tang, Jinglong, and Masaya Baba. "MiT/TFE Family Renal Cell Carcinoma." Genes 14, no. 1 (January 5, 2023): 151. http://dx.doi.org/10.3390/genes14010151.
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The microphthalmia-associated transcription factor/transcription factor E (MiT/TFE) family of transcription factors are evolutionarily conserved, basic helix–loop–helix leucine zipper (bHLH-Zip) transcription factors, consisting of MITF, TFEB, TFE3, and TFEC. MiT/TFE proteins, with the exception of TFEC, are involved in the development of renal cell carcinoma (RCC). Most of the MiT/TFE transcription factor alterations seen in sporadic RCC cases of MiT family translocation renal cell carcinoma (tRCC) are chimeric proteins generated by chromosomal rearrangements. These chimeric MiT/TFE proteins retain the bHLH-Zip structures and act as oncogenic transcription factors. The germline variant of MITF p.E318K has been reported as a risk factor for RCC. E 318 is present at the SUMOylation consensus site of MITF. The p.E318K variant abrogates SUMOylation on K 316, which results in alteration of MITF transcriptional activity. Only a few cases of MITF p.E318K RCC have been reported, and their clinical features have not yet been fully described. It would be important for clinicians to recognize MITF p.E318K RCC and consider MITF germline testing for undiagnosed familial RCC cases. This review outlines the involvement of the MiT/TFE transcription factors in RCC, both in sporadic and hereditary cases. Further elucidation of the molecular function of the MiT/TFE family is necessary for better diagnosis and treatment of these rare diseases.
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Orzechowska-Licari, Emilia J., Joseph F. LaComb, Aisharja Mojumdar, and Agnieszka B. Bialkowska. "SP and KLF Transcription Factors in Cancer Metabolism." International Journal of Molecular Sciences 23, no. 17 (September 1, 2022): 9956. http://dx.doi.org/10.3390/ijms23179956.
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Tumor development and progression depend on reprogramming of signaling pathways that regulate cell metabolism. Alterations to various metabolic pathways such as glycolysis, oxidative phosphorylation, lipid metabolism, and hexosamine biosynthesis pathway are crucial to sustain increased redox, bioenergetic, and biosynthesis demands of a tumor cell. Transcription factors (oncogenes and tumor suppressors) play crucial roles in modulating these alterations, and their functions are tethered to major metabolic pathways under homeostatic conditions and disease initiation and advancement. Specificity proteins (SPs) and Krüppel-like factors (KLFs) are closely related transcription factors characterized by three highly conserved zinc fingers domains that interact with DNA. Studies have demonstrated that SP and KLF transcription factors are expressed in various tissues and regulate diverse processes such as proliferation, differentiation, apoptosis, inflammation, and tumorigenesis. This review highlights the role of SP and KLF transcription factors in the metabolism of various cancers and their impact on tumorigenesis. A better understanding of the role and underlying mechanisms governing the metabolic changes during tumorigenesis could provide new therapeutic opportunities for cancer treatment.
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Lee, J. S., R. H. See, T. Deng, and Y. Shi. "Adenovirus E1A downregulates cJun- and JunB-mediated transcription by targeting their coactivator p300." Molecular and Cellular Biology 16, no. 8 (August 1996): 4312–26. http://dx.doi.org/10.1128/mcb.16.8.4312.
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Transcription factors and cofactors play critical roles in cell growth and differentiation. Alterations of their activities either through genetic mutations or by viral oncoproteins often result in aberrant cell growth and tumorigenesis. The transcriptional cofactor p300 has recently been shown to be complexed with transcription factors YY1 and CREB. Adenovirus E1A oncoproteins target these transcription complexes via physical interactions with p300, resulting in alterations of transcription mediated by these transcription factors. Here we show that p300 is also critical for repression by E1A of the activities of cJun and JunB, two members of the AP-1 transcriptional complexes. This repressive effect of E1A is dependent on the p300-binding domain of E1A and can be relieved by overexpression of p300. These results suggest that p300 serves as a mediator protein for downregulation of AP-1 activity by E1A. This hypothesis was further supported by the following observations: (i) in the absence of E1A, overexpression of p300 stimulated transcription both through an AP-1 site present in the collagenase promoter and through Jun proteins in GAL4 fusion protein-based assays; and (ii) overexpression of a mutant p300 lacking the E1A-interacting domain reduced the responsiveness of Jun-dependent transcription to E1A repression. As predicted from the functional results, p300 physically interacted with the Jun proteins. These findings thus established that p300 is a cofactor for cJun and JunB. We propose that p300 is a common mediator protein through which E1A gains control over multiple transcriptional regulatory pathways in the host cells.
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Wilson, Hannah E., David A. Stanton, Stephanie Rellick, Werner Geldenhuys, and Emidio E. Pistilli. "Breast cancer-associated skeletal muscle mitochondrial dysfunction and lipid accumulation is reversed by PPARG." American Journal of Physiology-Cell Physiology 320, no. 4 (April 1, 2021): C577—C590. http://dx.doi.org/10.1152/ajpcell.00264.2020.
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The peroxisome proliferator-activated receptors (PPARs) have been previously implicated in the pathophysiology of skeletal muscle dysfunction in women with breast cancer (BC) and animal models of BC. This study investigated alterations induced in skeletal muscle by BC-derived factors in an in vitro conditioned media (CM) system and tested the hypothesis that BC cells secrete a factor that represses PPAR-γ (PPARG) expression and its transcriptional activity, leading to downregulation of PPARG target genes involved in mitochondrial function and other metabolic pathways. We found that BC-derived factors repress PPAR-mediated transcriptional activity without altering protein expression of PPARG. Furthermore, we show that BC-derived factors induce significant alterations in skeletal muscle mitochondrial function and lipid accumulation, which are rescued with exogenous expression of PPARG. The PPARG agonist drug rosiglitazone was able to rescue BC-induced lipid accumulation but did not rescue effects of BC-derived factors on PPAR-mediated transcription or mitochondrial function. These data suggest that BC-derived factors alter lipid accumulation and mitochondrial function via different mechanisms that are both related to PPARG signaling, with mitochondrial dysfunction likely being altered via repression of PPAR-mediated transcription, and lipid accumulation being altered via transcription-independent functions of PPARG.
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Pazhani, Jayanthi, Vishnu Priya Veeraraghavan, and Selvaraj Jayaraman. "Transcription factors: a potential therapeutic target in head and neck squamous cell carcinoma." Epigenomics 15, no. 2 (January 2023): 57–60. http://dx.doi.org/10.2217/epi-2023-0046.
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Squamous cell carcinoma is the most common histopathological type of head and neck cancer; it often spreads to and involves the cervical lymph nodes. The tumorigenesis of head and neck squamous cell carcinoma (HNSCC) is a multistep process mediated by various transcription factors involved in progression and metastasis. Alterations in transcription factors such as FOSL1, YY1, FOXD1 and NF-κB have been associated with increased cell proliferation, cell migration and poor survival rates in patients with HNSCC. Stimulation of the NF-κB pathway results in transcriptional activation of other target genes associated with cell survival and proliferation. Understanding these molecular mechanisms will helps us develop new treatment strategies that target these transcription factors and may eventually decrease the morbidity and mortality associated with HNSCC.
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Koch, Marilin, Stefan Czemmel, Felix Lennartz, Sarah Beyeler, Justyna Przystal, Parameswari Govindarajan, Denis Canjuga, et al. "CSIG-15. INHIBITION OF THE bHLH TRANSCRIPTIONAL NETWORKS BY A MUTATED E47 PROTEIN LEADS TO A STRONG ANTI-GLIOMA ACTIVITY IN VITRO AND IN VIVO." Neuro-Oncology 21, Supplement_6 (November 2019): vi47. http://dx.doi.org/10.1093/neuonc/noz175.185.
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Abstract OBJECTIVE The transcription factor E47 heterodimerizes with helix-loop-helix (HLH) and basic helix-loop-helix transcription (bHLH) factors like ID-1 and Olig2 that are overexpressed in glioblastoma. A dominant-negative variant of the E47 (dnE47) lacking the nuclear translocation signal, leads to cytoplasmatic sequestration of HLH and bHLH transcription factors. Here, we investigated combinations of dnE47-mediated inhibition of the bHLH transcriptional network with temozolomide and irradiation and explored the underlying molecular mechanisms. METHODS Long-term and stem cell glioma lines were transduced with a Doxycycline-inducible dnE47 lentivirus. Functional characterizations included immunocytochemistry, immunoblots, cytotoxicity and clonogenicity assays in vitro and latency until the onset of symptoms in vivo. CAGE and RNASeq were conducted for analyzing the dnE47-induced molecular profile. RESULTS The induction of dnE47 led to cytoplasmatic sequestration of HLH/bHLH transcription, reduced proliferation, increased cytotoxicity and reduced clonogenic survival in vitro and a prolonged latency until the onset of neurological symptoms in vivo. CAGE and RNASeq data revealed alterations in several cancer-relevant pathways. CONCLUSIONS A dnE47-mediated inhibition of the bHLH transcription network induced actionable molecular alterations in glioma cells that could be exploited for the design of novel therapies.
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Goodson, Michael, Brian A. Jonas, and Martin A. Privalsky. "Corepressors: Custom Tailoring and Alterations While you Wait." Nuclear Receptor Signaling 3, no. 1 (January 2005): nrs.03003. http://dx.doi.org/10.1621/nrs.03003.
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A diverse cadre of metazoan transcription factors mediate repression by recruiting protein complexes containing the SMRT (silencing mediator of retinoid and thyroid hormone receptor) or N-CoR (nuclear receptor corepressor) corepressors. SMRT and N-CoR nucleate the assembly of still larger corepressor complexes that perform the specific molecular incantations necessary to confer transcriptional repression. Although SMRT and N-CoR are paralogs and possess similar molecular architectures and mechanistic strategies, they nonetheless exhibit distinct molecular and biological properties. It is now clear that the functions of both SMRT and N-CoR are further diversified through alternative mRNA splicing, yielding a series of corepressor protein variants that participate in distinctive transcription factor partnerships and display distinguishable repression properties. This review will discuss what is known about the structure and actions of SMRT, N-CoR, and their splicing variants, and how alternative splicing may allow the functions of these corepressors to be adapted and tailored to different cells and to different developmental stages.
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Zhu, Qian, Xavier Tekpli, Olga G. Troyanskaya, and Vessela N. Kristensen. "Subtype-specific transcriptional regulators in breast tumors subjected to genetic and epigenetic alterations." Bioinformatics 36, no. 4 (September 16, 2019): 994–99. http://dx.doi.org/10.1093/bioinformatics/btz709.
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Abstract Motivation Breast cancer consists of multiple distinct tumor subtypes, and results from epigenetic and genetic aberrations that give rise to distinct transcriptional profiles. Despite previous efforts to understand transcriptional deregulation through transcription factor networks, the transcriptional mechanisms leading to subtypes of the disease remain poorly understood. Results We used a sophisticated computational search of thousands of expression datasets to define extended signatures of distinct breast cancer subtypes. Using ENCODE ChIP-seq data of surrogate cell lines and motif analysis we observed that these subtypes are determined by a distinct repertoire of lineage-specific transcription factors. Furthermore, specific pattern and abundance of copy number and DNA methylation changes at these TFs and targets, compared to other genes and to normal cells were observed. Overall, distinct transcriptional profiles are linked to genetic and epigenetic alterations at lineage-specific transcriptional regulators in breast cancer subtypes. Availability and implementation The analysis code and data are deposited at https://bitbucket.org/qzhu/breast.cancer.tf/. Supplementary information Supplementary data are available at Bioinformatics online.
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Chen, Shali, Biao Feng, Biju George, Rana Chakrabarti, Megan Chen, and Subrata Chakrabarti. "Transcriptional coactivator p300 regulates glucose-induced gene expression in endothelial cells." American Journal of Physiology-Endocrinology and Metabolism 298, no. 1 (January 2010): E127—E137. http://dx.doi.org/10.1152/ajpendo.00432.2009.
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Sustained hyperglycemia in diabetes causes alteration of a large number of transcription factors and mRNA transcripts, leading to tissue damage. We investigated whether p300, a transcriptional coactivator with histone acetyl transferase activity, regulates glucose-induced activation of transcription factors and subsequent upregulation of vasoactive factors and extracellular matrix (ECM) proteins in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated in varied glucose concentrations and were studied after p300 small interfering RNA (siRNA) transfection, p300 overexpression, or incubation with the p300 inhibitor curcumin. Histone H2AX phosphorylation and lysine acetylation were examined for oxidative DNA damage and p300 activation. Screening for transcription factors was performed with the Luminex system. Alterations of selected transcription factors were validated. mRNA expression of p300, endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and fibronectin (FN) and its splice variant EDB+FN and FN protein production were analyzed. HUVECs in 25 mmol/l glucose showed increased p300 production accompanied by increased binding of p300 to ET-1 and FN promoters, augmented histone acetylation, H2AX phosphorylation, activation of multiple transcription factors, and increased mRNA expression of vasoactive factors and ECM proteins. p300 overexpression showed a glucose-like effect on the mRNA expression of ET-1, VEGF, and FN. Furthermore, siRNA-mediated p300 blockade or chemical inhibitor of p300 prevented such glucose-induced changes. Similar mRNA upregulation was also seen in the organ culture of vascular tissues, which was prevented by p300 siRNA transfection. Data from these studies suggest that glucose-induced p300 upregulation is an important upstream epigenetic mechanism regulating gene expression of vasoactive factors and ECM proteins in endothelial cells and is a potential therapeutic target for diabetic complications.
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Zhang, Dawn X., and Christopher K. Glass. "Towards an understanding of cell-specific functions of signal-dependent transcription factors." Journal of Molecular Endocrinology 51, no. 3 (October 15, 2013): T37—T50. http://dx.doi.org/10.1530/jme-13-0216.
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The ability to regulate gene expression in a cell-specific manner is a feature of many broadly expressed signal-dependent transcription factors (SDTFs), including nuclear hormone receptors and transcription factors that are activated by cell surface receptors for extracellular signals. As the most plastic cells of the hematopoietic system, macrophages are responsive to a wide spectrum of regulatory molecules and provide a robust model system for investigation of the basis for cell-specific transcriptional responses at a genome-wide level. Here, focusing on recent studies in macrophages, we review the evidence suggesting a model in which cell-specific actions of SDTFs are the consequence of priming functions of lineage determining transcription factors. We also discuss recent findings relating lineage-determining and SDTF activity to alterations in the epigenetic landscape as well as the production and function of enhancer RNAs. These findings have implications for the understanding of how natural genetic variation impacts cell-specific programs of gene expression and suggest new approaches for altering gene expressionin vivo.
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Rossi, Chiara, Anna Fernàndez, Pascual Torres, Omar Ramirez-Nuñez, Ana Belén Granado-Serrano, Laia Fontdevila, Mònica Povedano, Reinald Pamplona, Isidro Ferrer, and Manuel Portero-Otin. "Cell Stress Induces Mislocalization of Transcription Factors with Mitochondrial Enrichment." International Journal of Molecular Sciences 22, no. 16 (August 17, 2021): 8853. http://dx.doi.org/10.3390/ijms22168853.
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Previous evidence links the formation of extranuclear inclusions of transcription factors, such as ERK, Jun, TDP-43, and REST, with oxidative, endoplasmic-reticulum, proteasomal, and osmotic stress. To further characterize its extranuclear location, we performed a high-content screening based on confocal microscopy and automatized image analyses of an epithelial cell culture treated with hydrogen peroxide, thapsigargin, epoxomicin, or sorbitol at different concentrations and times to recreate the stresses mentioned above. We also performed a subcellular fractionation of the brain from transgenic mice overexpressing the Q331K-mutated TARDBP, and we analyzed the REST-regulated mRNAs. The results show that these nuclear proteins exhibit a mitochondrial location, together with significant nuclear/extranuclear ratio changes, in a protein and stress-specific manner. The presence of these proteins in enriched mitochondrial fractions in vivo confirmed the results of the image analyses. TDP-43 aggregation was associated with alterations in the mRNA levels of the REST target genes involved in calcium homeostasis, apoptosis, and metabolism. In conclusion, cell stress increased the mitochondrial translocation of nuclear proteins, increasing the chance of proteostasis alterations. Furthermore, TDP-43 aggregation impacts REST target genes, disclosing an exciting interaction between these two transcription factors in neurodegenerative processes.
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Zhang, Bo, Zhi-Wen Xu, Kun-Hao Wang, Tian-Cheng Lu, and Ye Du. "Complex Regulatory Network of MicroRNAs, Transcription Factors, Gene Alterations in Adrenocortical Cancer." Asian Pacific Journal of Cancer Prevention 14, no. 4 (April 30, 2013): 2265–68. http://dx.doi.org/10.7314/apjcp.2013.14.4.2265.
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Xu, Z., D. Cawthon, K. A. McCastlain, H. M. Duhart, G. D. Newport, H. Fang, T. A. Patterson, W. Slikker, and S. F. Ali. "Selective Alterations of Transcription Factors in MPP+-Induced Neurotoxicity in PC12 Cells." NeuroToxicology 26, no. 4 (August 2005): 729–37. http://dx.doi.org/10.1016/j.neuro.2004.12.008.
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Cook, Tiffany, and Raul Urrutia. "TIEG proteins join the Smads as TGF-β-regulated transcription factors that control pancreatic cell growth." American Journal of Physiology-Gastrointestinal and Liver Physiology 278, no. 4 (April 1, 2000): G513—G521. http://dx.doi.org/10.1152/ajpgi.2000.278.4.g513.
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The control of epithelial cell proliferation, differentiation, and apoptosis requires a balance between signaling and transcriptional regulation. Recent developments in pancreatic cell research have revealed that transforming growth factor-β (TGF-β) signaling is important for the regulation of each of these phenomena. More importantly, perturbations in this pathway are associated with pancreatic cancer. A chief example of these alterations is the mutation in the TGF-β-regulated transcription factor Smad4/DPC4 that is found in a large percentage of pancreatic tumors. Surprisingly, studies on transcription factors have remained an underrepresented area of pancreatic research. However, the discovery of Smad4/DPC4 as a transcription factor fueled further studies aimed at characterizing transcription factors involved in normal and neoplastic pancreatic cell growth. Our laboratory recently described the existence of a novel family of zinc finger transcription factors, TGF-β-inducible early-response gene (TIEG)1 and TIEG2, from the exocrine pancreas that, similarly to Smads, participate in the TGF-β response and inhibit epithelial cell proliferation. This review therefore focuses on describing the structure and function of these two families of transcription factor proteins that are becoming key players in the regulation of pancreatic cell growth.
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Liu, Shihua, Ya Qiu, Rong Xiang, and Peng Huang. "Characterization of H2O2-Induced Alterations in Global Transcription of mRNA and lncRNA." Antioxidants 11, no. 3 (March 3, 2022): 495. http://dx.doi.org/10.3390/antiox11030495.
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Hydrogen peroxide (H2O2) is an important reactive oxygen species that plays a major role in redox signaling. Although H2O2 is known to regulate gene expression and affect multiple cellular processes, the characteristics and mechanisms of such transcriptional regulation remain to be defined. In this study, we utilized transcriptome sequencing to determine the global changes of mRNA and lncRNA transcripts induced by H2O2 in human pancreatic normal epithelial (HPNE) and pancreatic cancer (PANC-1) cells. Promoter analysis using PROMO and TRRUST revealed that mRNAs and lncRNAs largely shared the same sets of transcription factors in response to ROS stress. Interestingly, promoters of the upregulated genes were similar to those of the downregulated transcripts, suggesting that the H2O2-responding promoters are conserved but they alone do not determine the levels of transcriptional outputs. We also found that H2O2 induced significant changes in molecules involved in the pathways of RNA metabolism, processing, and transport. Detailed analyses further revealed a significant difference between pancreatic cancer and noncancer cells in their response to H2O2 stress, especially in the transcription of genes involved in cell-cycle regulation and DNA repair. Our study provides new insights into RNA transcriptional regulation upon ROS stress in cancer and normal cells.
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Kgatle, Mankgopo M., Asgar A. Kalla, Muhammed M. Islam, Mike Sathekge, and Razia Moorad. "Prostate Cancer: Epigenetic Alterations, Risk Factors, and Therapy." Prostate Cancer 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/5653862.
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Prostate cancer (PCa) is the most prevalent urological cancer that affects aging men in South Africa, and mechanisms underlying prostate tumorigenesis remain elusive. Research advancements in the field of PCa and epigenetics have allowed for the identification of specific alterations that occur beyond genetics but are still critically important in the pathogenesis of tumorigenesis. Anomalous epigenetic changes associated with PCa include histone modifications, DNA methylation, and noncoding miRNA. These mechanisms regulate and silence hundreds of target genes including some which are key components of cellular signalling pathways that, when perturbed, promote tumorigenesis. Elucidation of mechanisms underlying epigenetic alterations and the manner in which these mechanisms interact in regulating gene transcription in PCa are an unmet necessity that may lead to novel chemotherapeutic approaches. This will, therefore, aid in developing combination therapies that will target multiple epigenetic pathways, which can be used in conjunction with the current conventional PCa treatment.
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Lefevre, Pascal, Svitlana Melnik, Nicola Wilson, Arthur D. Riggs, and Constanze Bonifer. "Developmentally Regulated Recruitment of Transcription Factors and Chromatin Modification Activities to Chicken Lysozyme cis-Regulatory Elements In Vivo." Molecular and Cellular Biology 23, no. 12 (June 15, 2003): 4386–400. http://dx.doi.org/10.1128/mcb.23.12.4386-4400.2003.
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ABSTRACT Expression of the chicken lysozyme gene is upregulated during macrophage differentiation and reaches its highest level in bacterial lipopolysaccharide (LPS)-stimulated macrophages. This is accompanied by complex alterations in chromatin structure. We have previously shown that chromatin fine-structure alterations precede the onset of gene expression in macrophage precursor cells and mark the lysozyme chromatin domain for expression later in development. To further examine this phenomenon and to investigate the basis for the differentiation-dependent alterations of lysozyme chromatin, we studied the recruitment of transcription factors to the lysozyme locus in vivo at different stages of myeloid differentiation. Factor recruitment occurred in several steps. First, early-acting transcription factors such as NF1 and Fli-1 bound to a subset of enhancer elements and recruited CREB-binding protein. LPS stimulation led to an additional recruitment of C/EBPβ and a significant change in enhancer and promoter structure. Transcription factor recruitment was accompanied by specific changes in histone modification within the lysozyme chromatin domain. Interestingly, we present evidence for a transient interaction of transcription factors with lysozyme chromatin in lysozyme-nonexpressing macrophage precursors, which was accompanied by a partial demethylation of CpG sites. This indicates that a partially accessible chromatin structure of lineage-specific genes is a hallmark of hematopoietic progenitor cells.
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Desvergne, Béatrice, Liliane Michalik, and Walter Wahli. "Transcriptional Regulation of Metabolism." Physiological Reviews 86, no. 2 (April 2006): 465–514. http://dx.doi.org/10.1152/physrev.00025.2005.
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Our understanding of metabolism is undergoing a dramatic shift. Indeed, the efforts made towards elucidating the mechanisms controlling the major regulatory pathways are now being rewarded. At the molecular level, the crucial role of transcription factors is particularly well-illustrated by the link between alterations of their functions and the occurrence of major metabolic diseases. In addition, the possibility of manipulating the ligand-dependent activity of some of these transcription factors makes them attractive as therapeutic targets. The aim of this review is to summarize recent knowledge on the transcriptional control of metabolic homeostasis. We first review data on the transcriptional regulation of the intermediary metabolism, i.e., glucose, amino acid, lipid, and cholesterol metabolism. Then, we analyze how transcription factors integrate signals from various pathways to ensure homeostasis. One example of this coordination is the daily adaptation to the circadian fasting and feeding rhythm. This section also discusses the dysregulations causing the metabolic syndrome, which reveals the intricate nature of glucose and lipid metabolism and the role of the transcription factor PPARγ in orchestrating this association. Finally, we discuss the molecular mechanisms underlying metabolic regulations, which provide new opportunities for treating complex metabolic disorders.
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Ries, Rhonda E., Hamid Bolouri, Jason E. Farrar, Emilia L. Lim, Timothy Junius Triche, Katherine Tarlock, Jaime Guidry Auvil, et al. "Alteration of Chromatin Modifiers and Misregulation of Transcription Factors Define the Genomic Profile of Infant AML." Blood 128, no. 22 (December 2, 2016): 774. http://dx.doi.org/10.1182/blood.v128.22.774.774.
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Abstract AML is a malignancy of hematopoietic progenitor cells characterized by differentiation arrest leading to hematopoietic insufficiency secondary to the accumulation of hematopoietic progenitors. While much is known about the karyotypic and immunophenotypic makeup of AML, comprehensive genomic data is still emerging. The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) AML project, a cooperative effort between the National Cancer Institute (NCI) and the Children's Oncology Group (COG), has sought to deepen the knowledge-base of genomic alterations that are present in childhood cancers. Sequence data from 918 children with AML was available, including 227 whole genome, 145 transcriptome, and 691 targeted exome capture. We identified 164 patients diagnosed with AML before the age of 2 years, which contributed to our study. From these data, the presence of fusions, somatic SNVs, and copy number alterations (for those with whole genome data) were assessed and evaluated in a pathway-centric analysis (TargetMine, http://targetmine.mizuguchilab.org). The OncoPrinter function (www.cbioportal.org) was used to visualize the mutations. Of the 164 patients <2 years of age, all but 3 (98%) had at least one detectable genomic alteration. In contrast to older patients, structural alterations were the predominant variants in this age group with 142 patients (87%) harboring translocations. The most prevalent fusion involved KMT2A (MLL) with 14 different partners in 45%, NUP98 fusions with 6 different fusion partners in 8%, and CBFA2T3-GLIS2 fusions in 7%. Other notable fusions include CBFB-MYH11 (6%), RUNX1 with 3 fusion partners (3%), RBM15-MKL1 (3%), and translocations involving ETV6 and KAT6A (2% each). In addition to fusions, copy number variations (CNVs) including deletions, duplications and copy-neutral LOH were observed in 33 patients (20%). Regions of involvement of these CNVs ranged from segmental intragenic CNVs to larger chromosomal gains, trisomy 19 or 21 among the most frequent (7% and 6%, respectively). Intragenic exon 8 and 9 deletion of the CBLgene was the most common intragenic abnormality observed in 5 patients (3%). Sequence variants including Single Nucleotide variants (SNVs) as well as insertions/deletions were detected in 102 patients (62%). Activating mutations of the RAS/MAPK signaling pathway were the predominant variants with prevalence of 46% (NRAS (18%), KRAS (14%), FLT3 (7%), KIT (3%), CBL and PTPN11 (5% each). Overall, 75 patients had a concomitant structural alteration and a RAS/MAPK variant, suggesting cooperation between these two class of variants. Additional sequence variants included mutations in WT1 (3%), CREBBP (2%), TET2 (2%), and GATA1 (2%). Known fusions involving KMT2A were seen in 76 patients (46%). Where genomic data were available, the site of breakpoint varied significantly within KMT2A (16 different breakpoints) ranging from 5' ATH motif to the 3' SET domain with 6/16 fusions clustering in the ring finger domain of the gene. KMT2A-SEPT6 fusion was seen in 6 patients (8%) and was uniquely detected in those <2 years of age (P<0.0001). In those with KMT2A fusions, additional CNVs involving KMT2Awere seen in 3 patients. Concomitant mutations in RAS activating signaling pathway were seen in 43 cases (57%). To determine whether these alterations were enriched in any functional pathways, genes involved in fusions/SNVs were uploaded in the TargetMine data warehouse and analyzed for pathway enrichment. Strikingly, 67% of all known fusions in this cohort contained a gene from the Chromatin Modifier classification including CREBBP, EP300, KAT6A, KDM5A, KMT2A, and NCOA2 and an additional 15% of fusion partners could be categorized as genes involved in transcriptional regulation (CBFB, ETV6, RUNX1, and PDGFRB). Likewise, 75% of all SNVs were enriched in pathways involving transcriptional regulation by TP53, (CREBBP, FLT3, GATA1, KIT, KMT2A, KRAS, NRAS, and WT1). Although sequence variants are the most common variants in older AML, structural alterations dominate the genomic landscape in children with AML <2 years of age with a prevalence of >90% (translocation or CNV). Cooperating mutations of the RAS/MAPK pathway appear to be the dominant variants that in cooperation with the chromatin modifying alterations might contribute to the leukemic initiation and progression. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Yang, Haopeng, and Michael R. Green. "Harnessing lymphoma epigenetics to improve therapies (article not eligible for CME credit)." Hematology 2020, no. 1 (December 4, 2020): 95–100. http://dx.doi.org/10.1182/hematology.2020006908.
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Abstract Affinity maturation and terminal differentiation of B cells via the germinal center reaction is a complex multistep process controlled by transcription factors that induce or suppress large dynamic transcriptional programs. This occurs via the recruitment of coactivator or corepressor complexes that epigenetically regulate gene expression by post-translationally modifying histones and/or remodeling chromatin structure. B-cell–intrinsic developmental programs both regulate and respond to interactions with other cells in the germinal center that provide survival and differentiation signals, such as T-follicular helper cells and follicular dendritic cells. Epigenetic and transcriptional programs that naturally occur during B-cell development are hijacked in B-cell lymphoma by genetic alterations that directly or indirectly change the function of transcription factors and/or chromatin-modifying genes. These in turn skew differentiation toward the tumor cell of origin and alter interactions between lymphoma B cells and other cells within the microenvironment. Understanding the mechanisms by which genetic alterations perturb epigenetic and transcriptional programs regulating B-cell development and immune interactions may identify opportunities to target these programs using epigenetic-modifying agents. Here, we discuss recently published studies centered on follicular lymphoma and diffuse large B-cell lymphoma within the context of prior knowledge, and we highlight how these insights have informed potential avenues for rational therapeutic interventions.
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Yang, Haopeng, and Michael R. Green. "Harnessing lymphoma epigenetics to improve therapies." Blood 136, no. 21 (November 19, 2020): 2386–91. http://dx.doi.org/10.1182/blood.2020006908.
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Abstract Affinity maturation and terminal differentiation of B cells via the germinal center reaction is a complex multistep process controlled by transcription factors that induce or suppress large dynamic transcriptional programs. This occurs via the recruitment of coactivator or corepressor complexes that epigenetically regulate gene expression by post-translationally modifying histones and/or remodeling chromatin structure. B-cell–intrinsic developmental programs both regulate and respond to interactions with other cells in the germinal center that provide survival and differentiation signals, such as T-follicular helper cells and follicular dendritic cells. Epigenetic and transcriptional programs that naturally occur during B-cell development are hijacked in B-cell lymphoma by genetic alterations that directly or indirectly change the function of transcription factors and/or chromatin-modifying genes. These in turn skew differentiation toward the tumor cell of origin and alter interactions between lymphoma B cells and other cells within the microenvironment. Understanding the mechanisms by which genetic alterations perturb epigenetic and transcriptional programs regulating B-cell development and immune interactions may identify opportunities to target these programs using epigenetic-modifying agents. Here, we discuss recently published studies centered on follicular lymphoma and diffuse large B-cell lymphoma within the context of prior knowledge, and we highlight how these insights have informed potential avenues for rational therapeutic interventions.
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Chen, Li, Moli Huang, Jasmine Plummer, Jian Pan, Yan Yi Jiang, Qian Yang, Tiago Chedraoui Silva, et al. "Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma." Gut 69, no. 4 (August 13, 2019): 630–40. http://dx.doi.org/10.1136/gutjnl-2019-318325.
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ObjectiveWhile oesophageal squamous cell carcinoma remains infrequent in Western populations, the incidence of oesophageal adenocarcinoma (EAC) has increased sixfold to eightfold over the past four decades. We aimed to characterise oesophageal cancer-specific and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs). DesignTo identify regulatory elements, we profiled fresh-frozen oesophageal normal samples, tumours and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modelling was performed to establish (super)-enhancers landscapes and interconnected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs were investigated by ChIP-Seq, circularised chromosome conformation capture sequencing and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo.ResultsWe found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of oesophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signalling pathways, some of which may be exploited pharmacologically (eg, leukemia inhibitory factor (LIF) pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by four master TFs—ELF3, KLF5, GATA6 and EHF—which promoted each other’s expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival.ConclusionsBy establishing cancer-specific and subtype-specific features of the EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.
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Yotova, Iveta, Emily Hsu, Catherine Do, Aulona Gaba, Matthias Sczabolcs, Sabine Dekan, Lukas Kenner, Rene Wenzl, and Benjamin Tycko. "Epigenetic Alterations Affecting Transcription Factors and Signaling Pathways in Stromal Cells of Endometriosis." PLOS ONE 12, no. 1 (January 26, 2017): e0170859. http://dx.doi.org/10.1371/journal.pone.0170859.
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Doerfler, Walter. "Adenovirus oncogenesis: alterations in cellular methylation and transcription patterns− factors in viral oncogenesis?" Gene Function & Disease 2, no. 4 (December 2001): 139–50. http://dx.doi.org/10.1002/1438-826x(200112)2:4<139::aid-gnfd139>3.0.co;2-8.
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Puustinen, Mikael Christer, and Lea Sistonen. "Molecular Mechanisms of Heat Shock Factors in Cancer." Cells 9, no. 5 (May 12, 2020): 1202. http://dx.doi.org/10.3390/cells9051202.
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Malignant transformation is accompanied by alterations in the key cellular pathways that regulate development, metabolism, proliferation and motility as well as stress resilience. The members of the transcription factor family, called heat shock factors (HSFs), have been shown to play important roles in all of these biological processes, and in the past decade it has become evident that their activities are rewired during tumorigenesis. This review focuses on the expression patterns and functions of HSF1, HSF2, and HSF4 in specific cancer types, highlighting the mechanisms by which the regulatory functions of these transcription factors are modulated. Recently developed therapeutic approaches that target HSFs are also discussed.
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Jeong, Mira, Min Luo, Deqiang Sun, Gretchen Darlington, Rebecca Hannah, Berthold Gottgens, Hui Wang, Rui Chen, Wei Li, and Margaret A. Goodell. "HSC Aging Epigenome: Widespread Alterations in DNA Methylation and Transcription." Blood 120, no. 21 (November 16, 2012): 2329. http://dx.doi.org/10.1182/blood.v120.21.2329.2329.
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Abstract Abstract 2329 Age is the most important risk factor for myelodysplastic syndrome (MDS), a premalignant state that transforms into acute myelogenous leukemia in one third of cases. Indeed with normal aging, hematopoietic stem cell (HSC) regenerative potential diminishes and differentiation skews from lymphopoiesis toward myelopoiesis. The expansion in the HSC pool with aging provides sufficient but abnormal blood production, and animals experience a decline in immune function. Previous studies from our lab established that the DNA methyltransferase 3a (Dnmt3a) enables efficient differentiation by critically regulating epigenetic silencing of HSC genes (Challen et al. 2012) Interestingly, Dnmt3a expression is decreased in old HSCs, leading us to hypothesize that epigenetic changes in old HSCs may partially mimic the changes seen in Dnmt3a mutant HSCs. We propose that revealing the genome-wide DNA methylation and transcriptome signatures will lead to a greater understanding of HSC aging and MDS, which is characterized by frequent epigenetic abnormalities. In this study, we investigated genome-wide DNA methylation and transcripts by whole genome bisulfite sequencing (WGBS) and transcriptome sequencing (mRNA-seq)in young and old HSCs. For WGBS, we generated ∼600M raw reads resulting in ∼ 60 raw Gb of paired-end sequence data and aligned them to either strand of the reference genome (mm9), providing an average 40-fold sequencing depth. Globally, there was a 1.1% difference in the DNA methylation between young and old HSCs. Of these differences, 38% (172,609) of the CpG dinucleotides were hypo-methylated, and 62% (275,557) were hyper-methylated in old HSCs. To understand where the methylation changes predominantly occurred, the genome was subdivided into 77 features. Among these features, SINEs, especially Alu elements, exhibited the highest level of DNA methylation (90.94% in young HSCs, and 91.87% in old HSCs). CpG islands (CGIs) adjacent to the transcription start sites (TSS) exhibited the lowest level of DNA methylation (2.02% in young HSCs, and 2.11% in old HSCs). Interestingly strong hypo-methylation was observed in ribosomal RNA regions (68.04% in young HSCs, 59.04% in old HSCs), and hyper-methylation was observed in LINEL1 repetitive elements (88.62% in young HSCs, 90.12% in old HSCs). Moreover, the examination of differentially methylated promoters identified enrichment of developmentally important transcription factors such as Gata2, Runx1, Gfi1b, Erg, Tal1 Eto2, Cebpa and Pu.1. Additionally, we compare our ∼10,000 differentially methylation regions (DMRs, regions with clustered DNA methylation changes) with a chip-seq data set containing binding of 160 ChIP-seq analyses of hematopoietic transcription factors in different hematopoietic cells. We found significant overlaps between DMRs and transcription factor binding regions. We found DMRs which were hypermethylated showed association with differentiation-promoting Ets factors, in particular Pu.1 from a range of different blood cell types. In contrast, hypomethylated DMRs showed associations with HSC-associated transcription factors such as Scl and Gata2. Further examination of the differentially methylated gene bodies, intragenic and intergenic DMRs identified some previously noted targets for epigenetic silencing or alteration in AML and also novel transcripts including long non-coding RNAs (lincRNA) and upstream regulatory elements (URE). We found significant correlation between RNA-seq expression and DMRs within +1kb upstream of TSS. RNA-sequencing provided complementary and distinct information about HSC aging. We identified differentially expressed genes, novel RNA transcripts, differential promoter, coding sequence, and splice variant usage with age. Gene set enrichment analysis of up- and down- regulated genes, revealed ribosomal protein and RNA metabolism as critical contributors to HSC aging. In conclusion, our study marks a milestone in the mouse HSC epigenome, reporting the first complete methylome and transcriptome of pure HSC using whole-genome bisulfite sequencing and RNA-seq. These provide novel information about the magnitude and specificity of age-related epigenetic changes in a well-defined HSC population. Understanding the roles of DNA methylation and transcription in normal HSC function will allow for greater therapeutic exploitation of HSCs in the clinic. Disclosures: No relevant conflicts of interest to declare.
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Crispino, John D., and Mitchell J. Weiss. "Erythro-megakaryocytic transcription factors associated with hereditary anemia." Blood 123, no. 20 (May 15, 2014): 3080–88. http://dx.doi.org/10.1182/blood-2014-01-453167.
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Abstract Most heritable anemias are caused by mutations in genes encoding globins, red blood cell (RBC) membrane proteins, or enzymes in the glycolytic and hexose monophosphate shunt pathways. A less common class of genetic anemia is caused by mutations that alter the functions of erythroid transcription factors (TFs). Many TF mutations associated with heritable anemia cause truncations or amino acid substitutions, resulting in the production of functionally altered proteins. Characterization of these mutant proteins has provided insights into mechanisms of gene expression, hematopoietic development, and human disease. Mutations within promoter or enhancer regions that disrupt TF binding to essential erythroid genes also cause anemia and heritable variations in RBC traits, such as fetal hemoglobin content. Defining the latter may have important clinical implications for de-repressing fetal hemoglobin synthesis to treat sickle cell anemia and β thalassemia. Functionally important alterations in genes encoding TFs or their cognate cis elements are likely to occur more frequently than currently appreciated, a hypothesis that will soon be tested through ongoing genome-wide association studies and the rapidly expanding use of global genome sequencing for human diagnostics. Findings obtained through such studies of RBCs and associated diseases are likely generalizable to many human diseases and quantitative traits.
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Chauhan, Gaurav, and Hannelore V. Heemers. "Somatic Alterations Impact AR Transcriptional Activity and Efficacy of AR-Targeting Therapies in Prostate Cancer." Cancers 13, no. 16 (August 5, 2021): 3947. http://dx.doi.org/10.3390/cancers13163947.
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Inhibiting the activity of the ligand-activated transcription factor androgen receptor (AR) is the default first-line treatment for metastatic prostate cancer (CaP). Androgen deprivation therapy (ADT) induces remissions, however, their duration varies widely among patients. The reason for this heterogeneity is not known. A better understanding of its molecular basis may improve treatment plans and patient survival. AR’s transcriptional activity is regulated in a context-dependent manner and relies on an interplay between its associated transcriptional regulators, DNA recognition motifs, and ligands. Alterations in one or more of these factors induce shifts in the AR cistrome and transcriptional output. Significant variability in AR activity is seen in both castration-sensitive (CS) and castration-resistant CaP (CRPC). Several AR transcriptional regulators undergo somatic alterations that impact their function in clinical CaPs. Some alterations occur in a significant fraction of cases, resulting in CaP subtypes, while others affect only a few percent of CaPs. Evidence is emerging that these alterations may impact the response to CaP treatments such as ADT, radiation therapy, and chemotherapy. Here, we review the contribution of recurring somatic alterations on AR cistrome and transcriptional output and the efficacy of CaP treatments and explore strategies to use these insights to improve treatment plans and outcomes for CaP patients.
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Belluti, Silvia, Giovanna Rigillo, and Carol Imbriano. "Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates." Cells 9, no. 3 (March 20, 2020): 760. http://dx.doi.org/10.3390/cells9030760.
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Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine.
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Bach, Duc-Hiep, Nguyen Long, Thi-Thu-Trang Luu, Nguyen Anh, Sung Kwon, and Sang Lee. "The Dominant Role of Forkhead Box Proteins in Cancer." International Journal of Molecular Sciences 19, no. 10 (October 22, 2018): 3279. http://dx.doi.org/10.3390/ijms19103279.
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Forkhead box (FOX) proteins are multifaceted transcription factors that are significantly implicated in cancer, with various critical roles in biological processes. Herein, we provide an overview of several key members of the FOXA, FOXC, FOXM1, FOXO and FOXP subfamilies. Important pathophysiological processes of FOX transcription factors at multiple levels in a context-dependent manner are discussed. We also specifically summarize some major aspects of FOX transcription factors in association with cancer research such as drug resistance, tumor growth, genomic alterations or drivers of initiation. Finally, we suggest that targeting FOX proteins may be a potential therapeutic strategy to combat cancer.
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Catizone, Allison N., Gizem Karsli Uzunbas, Petra Celadova, Sylvia Kuang, Daniel Bose, and Morgan A. Sammons. "Locally acting transcription factors regulate p53-dependent cis-regulatory element activity." Nucleic Acids Research 48, no. 8 (March 5, 2020): 4195–213. http://dx.doi.org/10.1093/nar/gkaa147.
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Abstract The master tumor suppressor p53 controls transcription of a wide-ranging gene network involved in apoptosis, cell cycle arrest, DNA damage repair, and senescence. Recent studies revealed pervasive binding of p53 to cis-regulatory elements (CREs), which are non-coding segments of DNA that spatially and temporally control transcription through the combinatorial binding of local transcription factors. Although the role of p53 as a strong trans-activator of gene expression is well known, the co-regulatory factors and local sequences acting at p53-bound CREs are comparatively understudied. We designed and executed a massively parallel reporter assay (MPRA) to investigate the effect of transcription factor binding motifs and local sequence context on p53-bound CRE activity. Our data indicate that p53-bound CREs are both positively and negatively affected by alterations in local sequence context and changes to co-regulatory TF motifs. Our data suggest p53 has the flexibility to cooperate with a variety of transcription factors in order to regulate CRE activity. By utilizing different sets of co-factors across CREs, we hypothesize that global p53 activity is guarded against loss of any one regulatory partner, allowing for dynamic and redundant control of p53-mediated transcription.
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Aliya, Nishat, Saifur Rahman, Zafar K. Khan, and Pooja Jain. "Cotranscriptional Chromatin Remodeling by Small RNA Species: An HTLV-1 Perspective." Leukemia Research and Treatment 2012 (February 9, 2012): 1–15. http://dx.doi.org/10.1155/2012/984754.
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Cell type specificity of human T cell leukemia virus 1 has been proposed as a possible reason for differential viral outcome in primary target cells versus secondary. Through chromatin remodeling, the HTLV-1 transactivator protein Tax interacts with cellular factors at the chromosomally integrated viral promoter to activate downstream genes and control viral transcription. RNA interference is the host innate defense mechanism mediated by short RNA species (siRNA or miRNA) that regulate gene expression. There exists a close collaborative functioning of cellular transcription factors with miRNA in order to regulate the expression of a number of eukaryotic genes including those involved in suppression of cell growth, induction of apoptosis, as well as repressing viral replication and propagation. In addition, it has been suggested that retroviral latency is influenced by chromatin alterations brought about by miRNA. Since Tax requires the assembly of transcriptional cofactors to carry out viral gene expression, there might be a close association between miRNA influencing chromatin alterations and Tax-mediated LTR activation. Herein we explore the possible interplay between HTLV-1 infection and miRNA pathways resulting in chromatin reorganization as one of the mechanisms determining HTLV-1 cell specificity and viral fate in different cell types.
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Khan, Zia A., and Subrata Chakrabarti. "Cellular Signaling and Potential New Treatment Targets in Diabetic Retinopathy." Experimental Diabetes Research 2007 (2007): 1–12. http://dx.doi.org/10.1155/2007/31867.
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Dysfunction and death of microvascular cells and imbalance between the production and the degradation of extracellular matrix (ECM) proteins are a characteristic feature of diabetic retinopathy (DR). Glucose-induced biochemical alterations in the vascular endothelial cells may activate a cascade of signaling pathways leading to increased production of ECM proteins and cellular dysfunction/death. Chronic diabetes leads to the activation of a number of signaling proteins including protein kinase C, protein kinase B, and mitogen-activated protein kinases. These signaling cascades are activated in response to hyperglycemia-induced oxidative stress, polyol pathway, and advanced glycation end product formation among others. The aberrant signaling pathways ultimately lead to activation of transcription factors such as nuclear factor-κB and activating protein-1. The activity of these transcription factors is also regulated by epigenetic mechanisms through transcriptional coactivator p300. These complex signaling pathways may be involved in glucose-induced alterations of endothelial cell phenotype leading to the production of increased ECM proteins and vasoactive effector molecules causing functional and structural changes in the microvasculature. Understanding of such mechanistic pathways will help to develop future adjuvant therapies for diabetic retinopathy.
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Felger, J. C., S. W. Cole, T. W. W. Pace, F. Hu, B. J. Woolwine, G. H. Doho, C. L. Raison, and A. H. Miller. "Molecular signatures of peripheral blood mononuclear cells during chronic interferon-α treatment: relationship with depression and fatigue." Psychological Medicine 42, no. 8 (December 9, 2011): 1591–603. http://dx.doi.org/10.1017/s0033291711002868.
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BackgroundInterferon-alpha (IFN-α) treatment for infectious disease and cancer causes high rates of depression and fatigue, and has been used to investigate the impact of inflammatory cytokines on brain and behavior. However, little is known about the transcriptional impact of chronic IFN-α on immune cellsin vivoand its relationship to IFN-α-induced behavioral changes.MethodGenome-wide transcriptional profiling was performed on peripheral blood mononuclear cells (PBMCs) from 21 patients with chronic hepatitis C virus (HCV) either awaiting IFN-α therapy (n=10) or at 12 weeks of IFN-α treatment (n=11).ResultsSignificance analysis of microarray data identified 252 up-regulated and 116 down-regulated gene transcripts. Of the up-regulated genes, 2′-5′-oligoadenylate synthetase 2 (OAS2), a gene linked to chronic fatigue syndrome (CFS), was the only gene that was differentially expressed in patients with IFN-α-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks (r=0.80,p=0.003 andr=0.70,p=0.017 respectively). Promoter-based bioinformatic analyses linked IFN-α-related transcriptional alterations to transcription factors involved in myeloid differentiation, IFN-α signaling, activator protein-1 (AP1) and cAMP responsive element binding protein/activation transcription factor (CREB/ATF) pathways, which were derived primarily from monocytes and plasmacytoid dendritic cells. IFN-α-treated patients with high depression/fatigue scores demonstrated up-regulation of genes bearing promoter motifs for transcription factors involved in myeloid differentiation, IFN-α and AP1 signaling, and reduced prevalence of motifs for CREB/ATF, which has been implicated in major depression.ConclusionsDepression and fatigue during chronic IFN-α administration were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including CFS and major depression, further supporting an immune contribution to these diseases.
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Divvela, Satya Srirama Karthik, Darius Saberi, and Beate Brand-Saberi. "Atoh8 in Development and Disease." Biology 11, no. 1 (January 14, 2022): 136. http://dx.doi.org/10.3390/biology11010136.
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Atoh8 belongs to a large superfamily of transcriptional regulators called basic helix-loop-helix (bHLH) proteins. bHLH proteins have been identified in a wide range of organisms from yeast to humans. The members of this special group of transcription factors were found to be involved not only in embryonic development but also in disease initiation and its progression. Given their importance in several fundamental processes, the translation, subcellular location and turnover of bHLH proteins is tightly regulated. Alterations in the expression of bHLH proteins have been associated with multiple diseases also in context with Atoh8 which seems to unfold its functions as both transcriptional activator and repressor. Like many other bHLH transcription factors, so far, Atoh8 has also been observed to be involved in both embryonic development and carcinogenesis where it mainly acts as tumor suppressor. This review summarizes our current understanding of Atoh8 structure, function and regulation and its complex and partially controversial involvement in development and disease.
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Gebrie, Alemu. "Transcription factor EB as a key molecular factor in human health and its implication in diseases." SAGE Open Medicine 11 (January 2023): 205031212311572. http://dx.doi.org/10.1177/20503121231157209.
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Transcription factor EB, as a component of the microphthalmia family of transcription factors, has been demonstrated to be a key controller of autophagy–lysosomal biogenesis. Transcription factor EB is activated by stressors such as nutrition and deprivation of growth factors, hypoxia, lysosomal stress, and mitochondrial injury. To achieve the ultimate functional state, it is controlled in a variety of modes, such as in its rate of transcription, post-transcriptional control, and post-translational alterations. Due to its versatile role in numerous signaling pathways, including the Wnt, calcium, AKT, and mammalian target of rapamycin complex 1 signaling pathways, transcription factor EB—originally identified to be an oncogene—is now well acknowledged as a regulator of a wide range of physiological systems, including autophagy–lysosomal biogenesis, response to stress, metabolism, and energy homeostasis. The well-known and recently identified roles of transcription factor EB suggest that this protein might play a central role in signaling networks in a number of non-communicable illnesses, such as cancer, cardiovascular disorders, drug resistance mechanisms, immunological disease, and tissue growth. The important developments in transcription factor EB research since its first description are described in this review. This review helps to advance transcription factor EB from fundamental research into therapeutic and regenerative applications by shedding light on how important a role it plays in human health and disease at the molecular level.
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Hayashi, Kaori. "Altered DNA methylation in kidney disease: useful markers and therapeutic targets." Clinical and Experimental Nephrology 26, no. 4 (January 13, 2022): 309–15. http://dx.doi.org/10.1007/s10157-022-02181-5.
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AbstractRecent studies have demonstrated the association of altered epigenomes with lifestyle-related diseases. Epigenetic regulation promotes biological plasticity in response to environmental changes, and such plasticity may cause a ‘memory effect’, a sustained effect of transient treatment or an insult in the course of lifestyle-related diseases. We investigated the significance of epigenetic changes in several genes required for renal integrity, including the nephrin gene in podocytes, and the sustained anti-proteinuric effect, focusing on the transcription factor Krüppel-like factor 4 (KLF4). We further reported the role of the DNA repair factor lysine-acetyl transferase 5 (KAT5), which acts coordinately with KLF4, in podocyte injury caused by a hyperglycemic state through the acceleration of DNA damage and epigenetic alteration. In contrast, KAT5 in proximal tubular cells prevents acute kidney injury via glomerular filtration regulation by an epigenetic mechanism as well as promotion of DNA repair, indicating the cell type-specific action and roles of DNA repair factors. This review summarizes epigenetic alterations in kidney diseases, especially DNA methylation, and their utility as markers and potential therapeutic targets. Focusing on transcription factors or DNA damage repair factors associated with epigenetic changes may be meaningful due to their cell-specific expression or action. We believe that a better understanding of epigenetic alterations in the kidney will lead to the development of a novel strategy for chronic kidney disease (CKD) treatment.
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Jones, Cheyenne A., William P. Tansey, and April M. Weissmiller. "Emerging Themes in Mechanisms of Tumorigenesis by SWI/SNF Subunit Mutation." Epigenetics Insights 15 (January 2022): 251686572211156. http://dx.doi.org/10.1177/25168657221115656.
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The SWI/SNF chromatin remodeling complex uses the energy of ATP hydrolysis to alter contacts between DNA and nucleosomes, allowing regions of the genome to become accessible for biological processes such as transcription. The SWI/SNF chromatin remodeler is also one of the most frequently altered protein complexes in cancer, with upwards of 20% of all cancers carrying mutations in a SWI/SNF subunit. Intense studies over the last decade have probed the molecular events associated with SWI/SNF dysfunction in cancer and common themes are beginning to emerge in how tumor-associated SWI/SNF mutations promote malignancy. In this review, we summarize current understanding of SWI/SNF complexes, their alterations in cancer, and what is known about the impact of these mutations on tumor-relevant transcriptional events. We discuss how enhancer dysregulation is a common theme in SWI/SNF mutant cancers and describe how resultant alterations in enhancer and super-enhancer activity conspire to block development and differentiation while promoting stemness and self-renewal. We also identify a second emerging theme in which SWI/SNF perturbations intersect with potent oncoprotein transcription factors AP-1 and MYC to drive malignant transcriptional programs.
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Cheng, Jinping, Guiqian Zhang, Linhao Xu, Chang Liu, and Hua Jiang. "Altered H3K27 trimethylation contributes to flowering time variations in polyploid Arabidopsis thaliana ecotypes." Journal of Experimental Botany 73, no. 5 (October 26, 2021): 1402–14. http://dx.doi.org/10.1093/jxb/erab470.
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Abstract Polyploidy is a widespread phenomenon in flowering plant species. Polyploid plants frequently exhibit considerable transcriptomic alterations after whole-genome duplication (WGD). It is known that the transcriptomic response to tetraploidization is ecotype-dependent in Arabidopsis; however, the biological significance and the underlying mechanisms are unknown. In this study, we found that 4x Col-0 presents a delayed flowering time whereas 4x Ler does not. The expression of FLOWERING LOCUS C (FLC), the major repressor of flowering, was significantly increased in 4x Col-0 but only a subtle change was present in 4x Ler. Moreover, the level of a repressive epigenetic mark, trimethylation of histone H3 at lysine 27 (H3K27me3), was significantly decreased in 4x Col-0 but not in 4x Ler, potentially leading to the differences in FLC transcription levels and flowering times. Hundreds of other genes in addition to FLC showed H3K27me3 alterations in 4x Col-0 and 4x Ler. LIKE HETEROCHROMATIN PROTEIN 1 (LHP1) and transcription factors required for H3K27me3 deposition presented transcriptional changes between the two ecotypes, potentially accounting for the different H3K27me3 alterations. We also found that the natural 4x Arabidopsis ecotype Wa-1 presented an early flowering time, which was associated with low expression of FLC. Taken together, our results demonstrate a role of H3K27me3 alterations in response to genome duplication in Arabidopsis autopolyploids, and that variation in flowering time potentially functions in autopolyploid speciation.
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Owen, R. D., and M. C. Ostrowski. "Rapid and selective alterations in the expression of cellular genes accompany conditional transcription of Ha-v-ras in NIH 3T3 cells." Molecular and Cellular Biology 7, no. 7 (July 1987): 2512–20. http://dx.doi.org/10.1128/mcb.7.7.2512-2520.1987.
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Hormone treatment of NIH 3T3 cells that contain recombinant fusions between the mouse mammary virus long terminal repeat and the v-ras gene of Harvey murine sarcoma virus results in conditional expression of the ras p21 gene product. Levels of ras mRNA and p21 are maximal after 2 to 4 h of hormone treatment. Analysis of cellular RNA by Northern blotting and nuclease S1 protection assays indicates that the expression of two cellular RNA species increases with kinetics similar to v-ras: v-sis-related RNA and retrovirus-related VL30 RNA. Run-on transcription in isolated nuclei shows that the increase in v-sis-related RNA is not dependent on transcription and therefore must arise by a post-transcriptional mechanism. The increase in VL30 expression is a transcriptional effect. Hormone treatment of normal NIH 3T3 cells has no effect on the expression of these DNA sequences. These results suggest that v-ras stimulation of autocrine factors may play a role in transformation of cells by this gene and also suggest a reverse genetic strategy to determine the nucleic acid sequences and cellular factors involved in the regulation of gene expression that is observed.
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Owen, R. D., and M. C. Ostrowski. "Rapid and selective alterations in the expression of cellular genes accompany conditional transcription of Ha-v-ras in NIH 3T3 cells." Molecular and Cellular Biology 7, no. 7 (July 1987): 2512–20. http://dx.doi.org/10.1128/mcb.7.7.2512.
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Hormone treatment of NIH 3T3 cells that contain recombinant fusions between the mouse mammary virus long terminal repeat and the v-ras gene of Harvey murine sarcoma virus results in conditional expression of the ras p21 gene product. Levels of ras mRNA and p21 are maximal after 2 to 4 h of hormone treatment. Analysis of cellular RNA by Northern blotting and nuclease S1 protection assays indicates that the expression of two cellular RNA species increases with kinetics similar to v-ras: v-sis-related RNA and retrovirus-related VL30 RNA. Run-on transcription in isolated nuclei shows that the increase in v-sis-related RNA is not dependent on transcription and therefore must arise by a post-transcriptional mechanism. The increase in VL30 expression is a transcriptional effect. Hormone treatment of normal NIH 3T3 cells has no effect on the expression of these DNA sequences. These results suggest that v-ras stimulation of autocrine factors may play a role in transformation of cells by this gene and also suggest a reverse genetic strategy to determine the nucleic acid sequences and cellular factors involved in the regulation of gene expression that is observed.
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Plaza-Diaz, Julio, David Izquierdo, Álvaro Torres-Martos, Aiman Tariq Baig, Concepción M. Aguilera, and Francisco Javier Ruiz-Ojeda. "Impact of Physical Activity and Exercise on the Epigenome in Skeletal Muscle and Effects on Systemic Metabolism." Biomedicines 10, no. 1 (January 7, 2022): 126. http://dx.doi.org/10.3390/biomedicines10010126.
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Exercise and physical activity induces physiological responses in organisms, and adaptations in skeletal muscle, which is beneficial for maintaining health and preventing and/or treating most chronic diseases. These adaptations are mainly instigated by transcriptional responses that ensue in reaction to each individual exercise, either resistance or endurance. Consequently, changes in key metabolic, regulatory, and myogenic genes in skeletal muscle occur as both an early and late response to exercise, and these epigenetic modifications, which are influenced by environmental and genetic factors, trigger those alterations in the transcriptional responses. DNA methylation and histone modifications are the most significant epigenetic changes described in gene transcription, linked to the skeletal muscle transcriptional response to exercise, and mediating the exercise adaptations. Nevertheless, other alterations in the epigenetics markers, such as epitranscriptomics, modifications mediated by miRNAs, and lactylation as a novel epigenetic modification, are emerging as key events for gene transcription. Here, we provide an overview and update of the impact of exercise on epigenetic modifications, including the well-described DNA methylations and histone modifications, and the emerging modifications in the skeletal muscle. In addition, we describe the effects of exercise on epigenetic markers in other metabolic tissues; also, we provide information about how systemic metabolism or its metabolites influence epigenetic modifications in the skeletal muscle.
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Khakhar, Arjun, Cecily Wang, Ryan Swanson, Sydney Stokke, Furva Rizvi, Surbhi Sarup, John Hobbs, and Daniel F. Voytas. "VipariNama: RNA viral vectors to rapidly elucidate the relationship between gene expression and phenotype." Plant Physiology 186, no. 4 (May 2, 2021): 2222–38. http://dx.doi.org/10.1093/plphys/kiab197.
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Abstract Synthetic transcription factors have great promise as tools to help elucidate relationships between gene expression and phenotype by allowing tunable alterations of gene expression without genomic alterations of the loci being studied. However, the years-long timescales, high cost, and technical skill associated with plant transformation have limited their use. In this work, we developed a technology called VipariNama (ViN) in which vectors based on the tobacco rattle virus are used to rapidly deploy Cas9-based synthetic transcription factors and reprogram gene expression in planta. We demonstrate that ViN vectors can implement activation or repression of multiple genes systemically and persistently over several weeks in Nicotiana benthamiana, Arabidopsis (Arabidopsis thaliana), and tomato (Solanum lycopersicum). By exploring strategies including RNA scaffolding, viral vector ensembles, and viral engineering, we describe how the flexibility and efficacy of regulation can be improved. We also show how this transcriptional reprogramming can create predictable changes to metabolic phenotypes, such as gibberellin biosynthesis in N. benthamiana and anthocyanin accumulation in Arabidopsis, as well as developmental phenotypes, such as plant size in N. benthamiana, Arabidopsis, and tomato. These results demonstrate how ViN vector-based reprogramming of different aspects of gibberellin signaling can be used to engineer plant size in a range of plant species in a matter of weeks. In summary, ViN accelerates the timeline for generating phenotypes from over a year to just a few weeks, providing an attractive alternative to transgenesis for synthetic transcription factor-enabled hypothesis testing and crop engineering.
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Ford, Heide L., Jessica Y. Hsu, Etienne P. Danis, Stephanie Nance, Jenean H. O’Brien, Annika L. Gustafson, Veronica M. Wessells, et al. "Abstract IA020: Reprogramming of myogenic transcription factors in rhabdomyosarcoma." Clinical Cancer Research 28, no. 18_Supplement (September 15, 2022): IA020. http://dx.doi.org/10.1158/1557-3265.sarcomas22-ia020.
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Abstract Rhabdomyosarcoma, a pediatric malignancy with partial resemblance to undifferentiated skeletal muscle, is characterized by high expression of myogenic-lineage transcription factors such as MYOD1 and MYOG. Despite high expression of these transcription factors, which in normal muscle result in differentiation, RMS cells fail to differentiate, suggesting the presence of factors that inhibit their normal differentiation-promoting functions. In this talk, I will present data that the key muscle transcriptional regulator, SIX1, which in development activates the myogenic regulatory factors (MRFs) and promotes muscle differentiation, in fact inhibits differentiation in fusion-negative (FN) RMS. SIX1 holds FN-RMS cells in a progenitor-like state by altering the chromatin landscape and causing MYOD1, a key MRF, to preferentially bind to regulatory regions of genes permissive to growth rather than differentiation. Loss of SIX1 results in re-localization of MYOD1 to promoters/enhancers of genes associated with differentiation, and further results in increased binding of MYOG at such loci. Altered binding of MYOD1 and MYOG in response to SIX1 loss results in marked inhibition of RMS growth in vivo, via induction of differentiation. These data suggest that SIX1 acts as a master regulatory factor controlling the fate of RMS cells. Data will be presented that suggest dynamic actions of SIX1 and its co-factors throughout normal muscle differentiation, whereby high levels of SIX1 expressed in early muscle differentiation may mimic a transcriptional state seen in RMS. We hypothesize that the specific levels of SIX1, combined with a unique combination of transcriptional co-factors, reprogram genome-wide binding of MRFs to different promoter/enhancer sites at specific developmental time points, and that RMS is trapped in an early developmental state where SIX1 represses differentiation via genome-wide alterations in MRF binding that favor growth. Understanding the co-factors that work with SIX1 to alter chromatin state and MRF binding may enable the discovery of novel targets whose inhibition could serve as a relatively non-toxic treatment to restore normal developmental processes and inhibit RMS progression. Citation Format: Heide L. Ford, Jessica Y. Hsu, Etienne P. Danis, Stephanie Nance, Jenean H. O’Brien, Annika L. Gustafson, Veronica M. Wessells, Andrew E. Goodspeed, Jared C. Talbot, Sharon L. Amacher, Paul Jedlicka, Joshua C. Black, James C. Costello, Adam D. Durbin, Kristin B. Artinger. Reprogramming of myogenic transcription factors in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA020.
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Ruiz-Roig, Clàudia, Núria Noriega, Alba Duch, Francesc Posas, and Eulàlia de Nadal. "The Hog1 SAPK controls the Rtg1/Rtg3 transcriptional complex activity by multiple regulatory mechanisms." Molecular Biology of the Cell 23, no. 21 (November 2012): 4286–96. http://dx.doi.org/10.1091/mbc.e12-04-0289.
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Cells modulate expression of nuclear genes in response to alterations in mitochondrial function, a response termed retrograde (RTG) regulation. In budding yeast, the RTG pathway relies on Rtg1 and Rtg3 basic helix-loop-helix leucine Zipper transcription factors. Exposure of yeast to external hyperosmolarity activates the Hog1 stress-activated protein kinase (SAPK), which is a key player in the regulation of gene expression upon stress. Several transcription factors, including Sko1, Hot1, the redundant Msn2 and Msn4, and Smp1, have been shown to be directly controlled by the Hog1 SAPK. The mechanisms by which Hog1 regulates their activity differ from one to another. In this paper, we show that Rtg1 and Rtg3 transcription factors are new targets of the Hog1 SAPK. In response to osmostress, RTG-dependent genes are induced in a Hog1-dependent manner, and Hog1 is required for Rtg1/3 complex nuclear accumulation. In addition, Hog1 activity regulates Rtg1/3 binding to chromatin and transcriptional activity. Therefore Hog1 modulates Rtg1/3 complex activity by multiple mechanisms in response to stress. Overall our data suggest that Hog1, through activation of the RTG pathway, contributes to ensure mitochondrial function as part of the Hog1-mediated osmoadaptive response.
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Tokola, Heikki, Nina Hautala, Minna Marttila, Jarkko Magga, Sampsa Pikkarainen, Risto Kerkelä, Olli Vuolteenaho, and Heikki Ruskoaho. "Mechanical load-induced alterations in B-type natriuretic peptide gene expression." Canadian Journal of Physiology and Pharmacology 79, no. 8 (August 1, 2001): 646–53. http://dx.doi.org/10.1139/y01-031.
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Atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide are the known members of the mammalian natriuretic peptide system. Like ANP, BNP is a natriuretic and diuretic hormone that also causes peripheral vasodilation and inhibition of the sympathetic and renin-angiotensin systems. Although originally isolated from porcine brain, the BNP gene is expressed in a specific manner in cardiac myocytes in both the atria and the ventricles, but it is mainly released from the ventricles. The major determinant of BNP secretion is wall stretch, and the levels of BNP mRNA increase substantially in response to cardiac overload. In the clinical setting, BNP appears to be the most powerful neurohumoral predictor of left-ventricular function and prognosis. An acute increase in BNP gene expression occurs within 1 h and mimics the rapid induction of proto-oncogenes in response to hemodynamic stress. BNP can be used as a myocyte-specific marker to identify mechanisms that couple acute mechanical overload to alterations in cardiac gene expression. This paper is focused on the mechanisms that regulate BNP gene expression in cardiac overload. Particularly, autocrine-paracrine factors as well as cytoplasmic signaling pathways and transcription factors involved in mechanical stretch-induced BNP gene expression are discussed.Key words: gene expression, mechanical load, natriuretic peptides, paracrine factors, transcription factors.
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Li, Shujing, and Luoying Zhang. "Circadian Control of Global Transcription." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/187809.
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Circadian rhythms exist in most if not all organisms on the Earth and manifest in various aspects of physiology and behavior. These rhythmic processes are believed to be driven by endogenous molecular clocks that regulate rhythmic expression of clock-controlled genes (CCGs). CCGs consist of a significant portion of the genome and are involved in diverse biological pathways. The transcription of CCGs is tuned by rhythmic actions of transcription factors and circadian alterations in chromatin. Here, we review the circadian control of CCG transcription in five model organisms that are widely used, including cyanobacterium, fungus, plant, fruit fly, and mouse. Comparing the similarity and differences in the five organisms could help us better understand the function of the circadian clock, as well as its output mechanisms adapted to meet the demands of diverse environmental conditions.
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Hu, Yangjie, Sotirios Fragkostefanakis, Enrico Schleiff, and Stefan Simm. "Transcriptional Basis for Differential Thermosensitivity of Seedlings of Various Tomato Genotypes." Genes 11, no. 6 (June 16, 2020): 655. http://dx.doi.org/10.3390/genes11060655.
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Transcriptional reprograming after the exposure of plants to elevated temperatures is a hallmark of stress response which is required for the manifestation of thermotolerance. Central transcription factors regulate the stress survival and recovery mechanisms and many of the core responses controlled by these factors are well described. In turn, pathways and specific genes contributing to variations in the thermotolerance capacity even among closely related plant genotypes are not well defined. A seedling-based assay was developed to directly compare the growth and transcriptome response to heat stress in four tomato genotypes with contrasting thermotolerance. The conserved and the genotype-specific alterations of mRNA abundance in response to heat stress were monitored after exposure to three different temperatures. The transcripts of the majority of genes behave similarly in all genotypes, including the majority of heat stress transcription factors and heat shock proteins, but also genes involved in photosynthesis and mitochondrial ATP production. In turn, genes involved in hormone and RNA-based regulation, such as auxin- and ethylene-related genes, or transcription factors like HsfA6b, show a differential regulation that associates with the thermotolerance pattern. Our results provide an inventory of genes likely involved in core and genotype-dependent heat stress response mechanisms with putative role in thermotolerance in tomato seedlings.
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Han, Songyan, Jun Lu, Yu Zhang, Cao Cheng, Liping Han, Xiuli Wang, Lin Li, Chunyan Liu, and Baiqu Huang. "Recruitment of histone deacetylase 4 by transcription factors represses interleukin-5 transcription." Biochemical Journal 400, no. 3 (November 28, 2006): 439–48. http://dx.doi.org/10.1042/bj20061085.
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The critical role of IL-5 (interleukin-5) in eosinophilic inflammation implicates it as a therapeutic target for allergic diseases. The aim of the present study was to elucidate the molecular basis for the involvement of reversible histone acetylation in IL-5 transcriptional regulation. We provide evidence that HDAC4 (histone deacetylase 4) and p300, a known HAT (histone acetyltransferase), reversibly controlled the activity of the IL-5 promoter in vivo and in vitro, with a concurrent alteration of histone H3 acetylation status at the promoter regions. The nucleo-cytoplasmic shuttling of HDAC4 was shown to play an important role in the suppressive function of HDAC4 in IL-5 gene expression. Point mutation and reporter ChIP (chromatin immunoprecipitation) studies determined that the four transcription factors binding on the IL-5 promoter, i.e. C/EBPβ (CAAT/enhancer-binding protein β), GATA3 (GATA binding protein 3), NFAT (nuclear factor of activated T cells) and YY1 (Yin and Yang 1), were essential for the recruitment of HDAC4. Consistent with these observations, HDAC4 was found to form protein complexes with GATA3 and YY1, and to co-exist in the nuclei with GATA3. We propose that the unique regulatory mechanism of IL-5 gene transcription involves the reversible histone modification catalysed by HDAC4 and p300, which are recruited by the transcription factors. The dynamic balance in IL-5 transcriptional regulation is achieved through interactions among HATs/HDACs, histones and transcription factors. These data contribute to understanding the molecular mechanisms of IL-5 regulation, which is crucial to the development of new therapeutic strategies for IL-5-related allergic diseases.
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Eguchi, Asuka, Garrett O. Lee, Fang Wan, Graham S. Erwin, and Aseem Z. Ansari. "Controlling gene networks and cell fate with precision-targeted DNA-binding proteins and small-molecule-based genome readers." Biochemical Journal 462, no. 3 (August 22, 2014): 397–413. http://dx.doi.org/10.1042/bj20140400.
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Transcription factors control the fate of a cell by regulating the expression of genes and regulatory networks. Recent successes in inducing pluripotency in terminally differentiated cells as well as directing differentiation with natural transcription factors has lent credence to the efforts that aim to direct cell fate with rationally designed transcription factors. Because DNA-binding factors are modular in design, they can be engineered to target specific genomic sequences and perform pre-programmed regulatory functions upon binding. Such precision-tailored factors can serve as molecular tools to reprogramme or differentiate cells in a targeted manner. Using different types of engineered DNA binders, both regulatory transcriptional controls of gene networks, as well as permanent alteration of genomic content, can be implemented to study cell fate decisions. In the present review, we describe the current state of the art in artificial transcription factor design and the exciting prospect of employing artificial DNA-binding factors to manipulate the transcriptional networks as well as epigenetic landscapes that govern cell fate.