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1
Braun, Christian J., Peter M. Bruno, Max A. Horlbeck, Luke A. Gilbert, Jonathan S. Weissman und Michael T. Hemann. „Versatile in vivo regulation of tumor phenotypes by dCas9-mediated transcriptional perturbation“. Proceedings of the National Academy of Sciences 113, Nr. 27 (20.06.2016): E3892—E3900. http://dx.doi.org/10.1073/pnas.1600582113.
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Targeted transcriptional regulation is a powerful tool to study genetic mediators of cellular behavior. Here, we show that catalytically dead Cas9 (dCas9) targeted to genomic regions upstream or downstream of the transcription start site allows for specific and sustainable gene-expression level alterations in tumor cells in vitro and in syngeneic immune-competent mouse models. We used this approach for a high-coverage pooled gene-activation screen in vivo and discovered previously unidentified modulators of tumor growth and therapeutic response. Moreover, by using dCas9 linked to an activation domain, we can either enhance or suppress target gene expression simply by changing the genetic location of dCas9 binding relative to the transcription start site. We demonstrate that these directed changes in gene-transcription levels occur with minimal off-target effects. Our findings highlight the use of dCas9-mediated transcriptional regulation as a versatile tool to reproducibly interrogate tumor phenotypes in vivo.
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Li, Conghui, Honghong Wang, Zhinang Yin, Pingping Fang, Ruijing Xiao, Ying Xiang, Wen Wang et al. „Ligand-induced native G-quadruplex stabilization impairs transcription initiation“. Genome Research 31, Nr. 9 (16.08.2021): 1546–60. http://dx.doi.org/10.1101/gr.275431.121.
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G-quadruplexes (G4s) are noncanonical DNA secondary structures formed through the self-association of guanines, and G4s are distributed widely across the genome. G4 participates in multiple biological processes including gene transcription, and G4-targeted ligands serve as potential therapeutic agents for DNA-targeted therapies. However, genome-wide studies of the exact roles of G4s in transcriptional regulation are still lacking. Here, we establish a sensitive G4-CUT&Tag method for genome-wide profiling of native G4s with high resolution and specificity. We find that native G4 signals are cell type–specific and are associated with transcriptional regulatory elements carrying active epigenetic modifications. Drug-induced promoter-proximal RNA polymerase II pausing promotes nearby G4 formation. In contrast, G4 stabilization by G4-targeted ligands globally reduces RNA polymerase II occupancy at gene promoters as well as nascent RNA synthesis. Moreover, ligand-induced G4 stabilization modulates chromatin states and impedes transcription initiation via inhibition of general transcription factors loading to promoters. Together, our study reveals a reciprocal genome-wide regulation between native G4 dynamics and gene transcription, which will deepen our understanding of G4 biology toward therapeutically targeting G4s in human diseases.
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Ahmed, Mahmoud, Trang Huyen Lai, Trang Minh Pham, Sahib Zada, Omar Elashkar, Jin Seok Hwang und Deok Ryong Kim. „Hierarchical regulation of autophagy during adipocyte differentiation“. PLOS ONE 17, Nr. 1 (26.01.2022): e0250865. http://dx.doi.org/10.1371/journal.pone.0250865.
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We previously showed that some adipogenic transcription factors such as CEBPB and PPARG directly and indirectly regulate autophagy gene expression in adipogenesis. The order and effect of these events are undetermined. In this study, we modeled the gene expression, DNA-binding of transcriptional regulators, and histone modifications during adipocyte differentiation and evaluated the effect of the regulators on gene expression in terms of direction and magnitude. Then, we identified the overlap of the transcription factors and co-factors binding sites and targets. Finally, we built a chromatin state model based on the histone marks and studied their relation to the factors’ binding. Adipogenic factors differentially regulated autophagy genes as part of the differentiation program. Co-regulators associated with specific transcription factors and preceded them to the regulatory regions. Transcription factors differed in the binding time and location, and their effect on expression was either localized or long-lasting. Adipogenic factors disproportionately targeted genes coding for autophagy-specific transcription factors. In sum, a hierarchical arrangement between adipogenic transcription factors and co-factors drives the regulation of autophagy during adipocyte differentiation.
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Scott, James N. F., Adam P. Kupinski und Joan Boyes. „Targeted genome regulation and modification using transcription activator-like effectors“. FEBS Journal 281, Nr. 20 (06.09.2014): 4583–97. http://dx.doi.org/10.1111/febs.12973.
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Huh, Hyunbin, Dong Kim, Han-Sol Jeong und Hyun Park. „Regulation of TEAD Transcription Factors in Cancer Biology“. Cells 8, Nr. 6 (17.06.2019): 600. http://dx.doi.org/10.3390/cells8060600.
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Transcriptional enhanced associate domain (TEAD) transcription factors play important roles during development, cell proliferation, regeneration, and tissue homeostasis. TEAD integrates with and coordinates various signal transduction pathways including Hippo, Wnt, transforming growth factor beta (TGFβ), and epidermal growth factor receptor (EGFR) pathways. TEAD deregulation affects well-established cancer genes such as KRAS, BRAF, LKB1, NF2, and MYC, and its transcriptional output plays an important role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance. To date, TEADs have been recognized to be key transcription factors of the Hippo pathway. Therefore, most studies are focused on the Hippo kinases and YAP/TAZ, whereas the Hippo-dependent and Hippo-independent regulators and regulations governing TEAD only emerged recently. Deregulation of the TEAD transcriptional output plays important roles in tumor progression and serves as a prognostic biomarker due to high correlation with clinicopathological parameters in human malignancies. In addition, discovering the molecular mechanisms of TEAD, such as post-translational modifications and nucleocytoplasmic shuttling, represents an important means of modulating TEAD transcriptional activity. Collectively, this review highlights the role of TEAD in multistep-tumorigenesis by interacting with upstream oncogenic signaling pathways and controlling downstream target genes, which provides unprecedented insight and rationale into developing TEAD-targeted anticancer therapeutics.
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Uprety, Bhawana, Amala Kaja, Jannatul Ferdoush, Rwik Sen und Sukesh R. Bhaumik. „Regulation of Antisense Transcription by NuA4 Histone Acetyltransferase and Other Chromatin Regulatory Factors“. Molecular and Cellular Biology 36, Nr. 6 (11.01.2016): 992–1006. http://dx.doi.org/10.1128/mcb.00808-15.
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NuA4 histone lysine (K) acetyltransferase (KAT) promotes transcriptional initiation of TATA-binding protein (TBP)-associated factor (TAF)-dependent ribosomal protein genes. TAFs have also been recently found to enhance antisense transcription from the 3′ end of theGAL10coding sequence. However, it remains unknown whether, like sense transcription of the ribosomal protein genes, TAF-dependent antisense transcription ofGAL10also requires NuA4 KAT. Here, we show that NuA4 KAT associates with theGAL10antisense transcription initiation site at the 3′ end of the coding sequence. Such association of NuA4 KAT depends on the Reb1p-binding site that recruits Reb1p activator to theGAL10antisense transcription initiation site. Targeted recruitment of NuA4 KAT to theGAL10antisense transcription initiation site promotesGAL10antisense transcription. Like NuA4 KAT, histone H3 K4/36 methyltransferases and histone H2B ubiquitin conjugase facilitateGAL10antisense transcription, while the Swi/Snf and SAGA chromatin remodeling/modification factors are dispensable for antisense, but not sense, transcription ofGAL10. Taken together, our results demonstrate for the first time the roles of NuA4 KAT and other chromatin regulatory factors in controlling antisense transcription, thus illuminating chromatin regulation of antisense transcription.
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Perez-Oquendo, Mabel, und Don L. Gibbons. „Regulation of ZEB1 Function and Molecular Associations in Tumor Progression and Metastasis“. Cancers 14, Nr. 8 (07.04.2022): 1864. http://dx.doi.org/10.3390/cancers14081864.
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Zinc finger E-box binding homeobox 1 (ZEB1) is a pleiotropic transcription factor frequently expressed in carcinomas. ZEB1 orchestrates the transcription of genes in the control of several key developmental processes and tumor metastasis via the epithelial-to-mesenchymal transition (EMT). The biological function of ZEB1 is regulated through pathways that influence its transcription and post-transcriptional mechanisms. Diverse signaling pathways converge to induce ZEB1 activity; however, only a few studies have focused on the molecular associations or functional changes of ZEB1 by post-translational modifications (PTMs). Due to the robust effect of ZEB1 as a transcription repressor of epithelial genes during EMT, the contribution of PTMs in the regulation of ZEB1-targeted gene expression is an active area of investigation. Herein, we review the pivotal roles that phosphorylation, acetylation, ubiquitination, sumoylation, and other modifications have in regulating the molecular associations and behavior of ZEB1. We also outline several questions regarding the PTM-mediated regulation of ZEB1 that remain unanswered. The areas of research covered in this review are contributing to new treatment strategies for cancer by improving our mechanistic understanding of ZEB1-mediated EMT.
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Imoberdorf, Rachel Maria, Irini Topalidou und Michel Strubin. „A Role for Gcn5-Mediated Global Histone Acetylation in Transcriptional Regulation“. Molecular and Cellular Biology 26, Nr. 5 (01.03.2006): 1610–16. http://dx.doi.org/10.1128/mcb.26.5.1610-1616.2006.
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ABSTRACT Transcriptional activators often require histone acetyltransferases (HATs) for full activity. The common explanation is that activators directly recruit HATs to gene promoters to locally hyperacetylate histones and thereby facilitate transcription complex formation. However, in addition to being targeted to specific loci, HATs such as Gcn5 also modify histones genome-wide. Here we provide evidence for a role of this global HAT activity in regulated transcription. We show that activation by direct recruitment of the transcriptional machinery neither recruits Gcn5 nor induces changes in histone acetylation yet can strongly depend on Gcn5 at promoters showing a high basal state of Gcn5-mediated histone acetylation. We also show that Gcn5 dependency varies among core promoters and is influenced by the strength of interaction used to recruit the machinery and by the affinity of the latter for the core promoter. These data support a role for global Gcn5 HAT activity in modulating transcription independently of its known coactivator function.
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Nourani, Amine, Yannick Doyon, Rhea T. Utley, Stéphane Allard, William S. Lane und Jacques Côté. „Role of an ING1 Growth Regulator in Transcriptional Activation and Targeted Histone Acetylation by the NuA4 Complex“. Molecular and Cellular Biology 21, Nr. 22 (15.11.2001): 7629–40. http://dx.doi.org/10.1128/mcb.21.22.7629-7640.2001.
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ABSTRACT The yeast NuA4 complex is a histone H4 and H2A acetyltransferase involved in transcription regulation and essential for cell cycle progression. We identify here a novel subunit of the complex, Yng2p, a plant homeodomain (PHD)-finger protein homologous to human p33/ING1, which has tumor suppressor activity and is essential for p53 function. Mass spectrometry, immunoblotting, and immunoprecipitation experiments confirm the stable stoichiometric association of this protein with purified NuA4. Yeast cells harboring a deletion of theYNG2 gene show severe growth phenotype and have gene-specific transcription defects. NuA4 complex purified from the mutant strain is low in abundance and shows weak histone acetyltransferase activity. We demonstrate conservation of function by the requirement of Yng2p for p53 to function as a transcriptional activator in yeast. Accordingly, p53 interacts with NuA4 in vitro and in vivo, an interaction reminiscent of the p53-ING1 physical link in human cells. The growth defect of Δyng2 cells can be rescued by the N-terminal part of the protein, lacking the PHD-finger. While Yng2 PHD-finger is not required for p53 interaction, it is necessary for full expression of the p53-responsive gene and other NuA4 target genes. Transcriptional activation by p53 in vivo is associated with targeted NuA4-dependent histone H4 hyperacetylation, while histone H3 acetylation levels remain unchanged. These results emphasize the essential role of the NuA4 complex in the control of cell proliferation through gene-specific transcription regulation. They also suggest that regulation of mammalian cell proliferation by p53-dependent transcriptional activation functions through recruitment of an ING1-containing histone acetyltransferase complex.
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Zhang, Yixin, Yanlan Mo, Liyuan Han, Zhenyuan Sun und Wenzhong Xu. „Exploring Transcriptional Regulation of Hyperaccumulation in Sedum plumbizincicola through Integrated Transcriptome Analysis and CRISPR/Cas9 Technology“. International Journal of Molecular Sciences 24, Nr. 14 (24.07.2023): 11845. http://dx.doi.org/10.3390/ijms241411845.
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The cadmium hyperaccumulator Sedum plumbizincicola has remarkable abilities for cadmium (Cd) transport, accumulation and detoxification, but the transcriptional regulation mechanisms responsible for its Cd hyperaccumulation remain unknown. To address this knowledge gap, we conducted a comparative transcriptome study between S. plumbizincicola and the non-hyperaccumulating ecotype (NHE) of Sedum alfredii with or without Cd treatment. Our results revealed many differentially expressed genes involved in heavy metal transport and detoxification that were abundantly expressed in S. plumbizincicola. Additionally, we identified a large number of differentially expressed transcription factor genes, highlighting the complexity of transcriptional regulatory networks. We further screened four transcription factor genes that were highly expressed in the roots of S. plumbizincicola as candidate genes for creating CRISPR/Cas9 knockout mutations. Among these, the SpARR11 and SpMYB84 mutant lines exhibited decreased Cd accumulation in their aboveground parts, suggesting that these two transcription factors may play a role in the regulation of the Cd hyperaccumulation in S. plumbizincicola. Although further research will be required to determine the precise targeted genes of these transcription factors, combined transcriptome analysis and CRISPR/Cas9 technology provides unprecedented opportunities for identifying transcription factors related to Cd hyperaccumulation and contributes to the understanding of the transcriptional regulation mechanism of hyperaccumulation in S. plumbizincicola.
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Liu, Liu, Shasha Yin, Charles Brobbey und Wenjian Gan. „Ubiquitination in cancer stem cell: roles and targeted cancer therapy“. STEMedicine 1, Nr. 3 (30.03.2020): e37. http://dx.doi.org/10.37175/stemedicine.v1i3.37.
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Cancer stem cells (CSCs) are a small subset of stem-like cells inside tumors, which possess abilities of unlimited self-renewal, differentiation and proliferation. Extensive studies have suggested that CSCs are one of the major drivers of tumor initiation, metastasis, relapse and therapeutic resistance. Several regulatory networks including transcriptional programs and various signaling pathways tightly control the stemness, proliferation and differentiation of CSCs. Emerging evidence has indicated that post-translational modifications, especially ubiquitination, play a critical role in maintenance of CSC properties. In this review, we summarize current understandings on E3 ubiquitin ligase-mediated regulation of transcription factors and key signaling pathways involved in the regulation of CSCs, and discuss the strategy to target CSCs and E3 ubiquitin ligases for combating cancers.
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Chapman, Brittany, Jeong Hoon Han, Hong Jo Lee, Isabella Ruud und Tae Hyun Kim. „Targeted Modulation of Chicken Genes In Vitro Using CRISPRa and CRISPRi Toolkit“. Genes 14, Nr. 4 (13.04.2023): 906. http://dx.doi.org/10.3390/genes14040906.
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Engineering of clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9) system has enabled versatile applications of CRISPR beyond targeted DNA cleavage. Combination of nuclease-deactivated Cas9 (dCas9) and transcriptional effector domains allows activation (CRISPRa) or repression (CRISPRi) of target loci. To demonstrate the effectiveness of the CRISPR-mediated transcriptional regulation in chickens, three CRISPRa (VP64, VPR, and p300) and three CRISPRi (dCas9, dCas9-KRAB, and dCas9-KRAB-MeCP2) systems were tested in chicken DF-1 cells. By introducing guide RNAs (gRNAs) targeting near the transcription start site (TSS) of each gene in CRISPRa and CRISPRi effector domain-expressing chicken DF-1 cell lines, significant gene upregulation was induced in dCas9-VPR and dCas9-VP64 cells, while significant downregulation was observed with dCas9 and dCas9-KRAB. We further investigated the effect of gRNA positions across TSS and discovered that the location of gRNA is an important factor for targeted gene regulation. RNA sequencing analysis of IRF7 CRISPRa and CRISPRi- DF-1 cells revealed the specificity of CRISPRa and CRISPRi-based targeted transcriptional regulation with minimal off-target effects. These findings suggest that the CRISPRa and CRISPRi toolkits are an effective and adaptable platform for studying the chicken genome by targeted transcriptional modulation.
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Jouvenot, Y., V. Ginjala, L. Zhang, P.-Q. Liu, M. Oshimura, A. P. Feinberg, A. P. Wolffe, Rolf Ohlsson und P. D. Gregory. „Targeted regulation of imprinted genes by synthetic zinc-finger transcription factors“. Gene Therapy 10, Nr. 6 (März 2003): 513–22. http://dx.doi.org/10.1038/sj.gt.3301930.
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Porter, Baylee A., Maria A. Ortiz, Gennady Bratslavsky und Leszek Kotula. „Structure and Function of the Nuclear Receptor Superfamily and Current Targeted Therapies of Prostate Cancer“. Cancers 11, Nr. 12 (23.11.2019): 1852. http://dx.doi.org/10.3390/cancers11121852.
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The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival, and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, we utilize the initial classification system, which defines subfamilies based on structure and functional difference. The defining feature of the nuclear receptor superfamily is that these proteins function as transcription factors. The loss of transcriptional regulation or gain of functioning of these receptors is a hallmark in numerous diseases. For example, in prostate cancer, the androgen receptor is a primary target for current prostate cancer therapies. Targeted cancer therapies for nuclear hormone receptors have been more feasible to develop than others due to the ligand availability and cell permeability of hormones. To better target these receptors, it is critical to understand their structural and functional regulation. Given that late-stage cancers often develop hormone insensitivity, we will explore the strengths and pitfalls of targeting other transcription factors outside of the nuclear receptor superfamily such as the signal transducer and activator of transcription (STAT).
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Aranda, Sergi, Gloria Mas und Luciano Di Croce. „Regulation of gene transcription by Polycomb proteins“. Science Advances 1, Nr. 11 (Dezember 2015): e1500737. http://dx.doi.org/10.1126/sciadv.1500737.
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The Polycomb group (PcG) of proteins defines a subset of factors that physically associate and function to maintain the positional identity of cells from the embryo to adult stages. PcG has long been considered a paradigmatic model for epigenetic maintenance of gene transcription programs. Despite intensive research efforts to unveil the molecular mechanisms of action of PcG proteins, several fundamental questions remain unresolved: How many different PcG complexes exist in mammalian cells? How are PcG complexes targeted to specific loci? How does PcG regulate transcription? In this review, we discuss the diversity of PcG complexes in mammalian cells, examine newly identified modes of recruitment to chromatin, and highlight the latest insights into the molecular mechanisms underlying the function of PcGs in transcription regulation and three-dimensional chromatin conformation.
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Perrella, Giorgio, Mhairi L. H. Davidson, Liz O’Donnell, Ana-Marie Nastase, Pawel Herzyk, Ghislain Breton, Jose L. Pruneda-Paz, Steve A. Kay, Joanne Chory und Eirini Kaiserli. „ZINC-FINGER interactions mediate transcriptional regulation of hypocotyl growth in Arabidopsis“. Proceedings of the National Academy of Sciences 115, Nr. 19 (23.04.2018): E4503—E4511. http://dx.doi.org/10.1073/pnas.1718099115.
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Integration of environmental signals and interactions among photoreceptors and transcriptional regulators is key in shaping plant development. TANDEM ZINC-FINGER PLUS3 (TZP) is an integrator of light and photoperiodic signaling that promotes flowering in Arabidopsis thaliana. Here we elucidate the molecular role of TZP as a positive regulator of hypocotyl elongation. We identify an interacting partner for TZP, the transcription factor ZINC-FINGER HOMEODOMAIN 10 (ZFHD10), and characterize its function in coregulating the expression of blue-light–dependent transcriptional regulators and growth-promoting genes. By employing a genome-wide approach, we reveal that ZFHD10 and TZP coassociate with promoter targets enriched in light-regulated elements. Furthermore, using a targeted approach, we show that ZFHD10 recruits TZP to the promoters of key coregulated genes. Our findings not only unveil the mechanism of TZP action in promoting hypocotyl elongation at the transcriptional level but also assign a function to an uncharacterized member of the ZFHD transcription factor family in promoting plant growth.
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Shao, Jiawei, Meiyan Wang, Guiling Yu, Sucheng Zhu, Yuanhuan Yu, Boon Chin Heng, Jiali Wu und Haifeng Ye. „Synthetic far-red light-mediated CRISPR-dCas9 device for inducing functional neuronal differentiation“. Proceedings of the National Academy of Sciences 115, Nr. 29 (02.07.2018): E6722—E6730. http://dx.doi.org/10.1073/pnas.1802448115.
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The ability to control the activity of CRISPR-dCas9 with precise spatiotemporal resolution will enable tight genome regulation of user-defined endogenous genes for studying the dynamics of transcriptional regulation. Optogenetic devices with minimal phototoxicity and the capacity for deep tissue penetration are extremely useful for precise spatiotemporal control of cellular behavior and for future clinic translational research. Therefore, capitalizing on synthetic biology and optogenetic design principles, we engineered a far-red light (FRL)-activated CRISPR-dCas9 effector (FACE) device that induces transcription of exogenous or endogenous genes in the presence of FRL stimulation. This versatile system provides a robust and convenient method for precise spatiotemporal control of endogenous gene expression and also has been demonstrated to mediate targeted epigenetic modulation, which can be utilized to efficiently promote differentiation of induced pluripotent stem cells into functional neurons by up-regulating a single neural transcription factor, NEUROG2. This FACE system might facilitate genetic/epigenetic reprogramming in basic biological research and regenerative medicine for future biomedical applications.
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Chuang, Kai-Ting, Shyh-Shin Chiou und Shih-Hsien Hsu. „Recent Advances in Transcription Factors Biomarkers and Targeted Therapies Focusing on Epithelial–Mesenchymal Transition“. Cancers 15, Nr. 13 (25.06.2023): 3338. http://dx.doi.org/10.3390/cancers15133338.
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Transcription factors involve many proteins in the process of transactivating or transcribing (none-) encoded DNA to initiate and regulate downstream signals, such as RNA polymerase. Their unique characteristic is that they possess specific domains that bind to specific DNA element sequences called enhancer or promoter sequences. Epithelial–mesenchymal transition (EMT) is involved in cancer progression. Many dysregulated transcription factors—such as Myc, SNAIs, Twists, and ZEBs—are key drivers of tumor metastasis through EMT regulation. This review summarizes currently available evidence related to the oncogenic role of classified transcription factors in EMT editing and epigenetic regulation, clarifying the roles of the classified conserved transcription factor family involved in the EMT and how these factors could be used as therapeutic targets in future investigations.
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Hirsch, Matthew, und Thomas Elliott. „Stationary-Phase Regulation of RpoS Translation in Escherichia coli“. Journal of Bacteriology 187, Nr. 21 (01.11.2005): 7204–13. http://dx.doi.org/10.1128/jb.187.21.7204-7213.2005.
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ABSTRACT In enteric bacteria, adaptation to a number of different stresses is mediated by the RpoS protein, one of several sigma factors that collectively allow a tailored transcriptional response to environmental cues. Stress stimuli including low temperature, osmotic shock, nutrient limitation, and growth to stationary phase (SP) all result in a substantial increase in RpoS abundance and activity. The mechanism of regulation depends on the specific signal but may occur at the level of transcription, translation, protein activity, or targeted proteolysis. In both Escherichia coli and Salmonella enterica, SP induction of RpoS in rich medium is >30 fold and includes effects on both transcription and translation. Recently, we found that SP control of rpoS transcription in S. enterica involves repression of the major rpoS promoter during exponential phase by the global transcription factor Fis. Working primarily with E. coli, we now show that 24 nucleotides of the rpoS ribosome-binding site (RBS) are necessary and sufficient for a large part of the increase in rpoS translation as cells grow to SP. Genetic evidence points to an essential role for the leader nucleotides just upstream of the Shine-Dalgarno sequence but is conflicted on the question of whether sequence or structure is important. SP regulation of rpoS is conserved between E. coli and S. enterica. When combined with an fis mutation to block transcriptional effects, replacement of the rpoS RBS sequence by the lacZ RBS eliminates nearly all SP induction of RpoS.
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Neely, Lori A., und Charles S. Hoffman. „Protein Kinase A and Mitogen-Activated Protein Kinase Pathways Antagonistically Regulate Fission Yeast fbp1Transcription by Employing Different Modes of Action at Two Upstream Activation Sites“. Molecular and Cellular Biology 20, Nr. 17 (01.09.2000): 6426–34. http://dx.doi.org/10.1128/mcb.20.17.6426-6434.2000.
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ABSTRACT A significant challenge to our understanding of eukaryotic transcriptional regulation is to determine how multiple signal transduction pathways converge on a single promoter to regulate transcription in divergent fashions. To study this, we have investigated the transcriptional regulation of theSchizosaccharomyces pombe fbp1 gene that is repressed by a cyclic AMP (cAMP)-dependent protein kinase A (PKA) pathway and is activated by a stress-activated mitogen-activated protein kinase (MAPK) pathway. In this study, we identified and characterized twocis-acting elements in the fbp1 promoter required for activation of fbp1 transcription. Upstream activation site 1 (UAS1), located approximately 900 bp from the transcriptional start site, resembles a cAMP response element (CRE) that is the binding site for the atf1-pcr1 heterodimeric transcriptional activator. Binding of this activator to UAS1 is positively regulated by the MAPK pathway and negatively regulated by PKA. UAS2, located approximately 250 bp from the transcriptional start site, resembles a Saccharomyces cerevisiae stress response element. UAS2 is bound by transcriptional activators and repressors regulated by both the PKA and MAPK pathways, although atf1 itself is not present in these complexes. Transcriptional regulation offbp1 promoter constructs containing only UAS1 or UAS2 confirms that the PKA and MAPK regulation is targeted to both sites. We conclude that the PKA and MAPK signal transduction pathways regulatefbp1 transcription at UAS1 and UAS2, but that the antagonistic interactions between these pathways involve different mechanisms at each site.
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Luikenhuis, Sandra, Anton Wutz und Rudolf Jaenisch. „Antisense Transcription through theXist Locus Mediates Tsix Function in Embryonic Stem Cells“. Molecular and Cellular Biology 21, Nr. 24 (15.12.2001): 8512–20. http://dx.doi.org/10.1128/mcb.21.24.8512-8520.2001.
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ABSTRACT Expression of the Xist gene, a key player in mammalian X inactivation, has been proposed to be controlled by the antisense Tsix transcript. Targeted deletion of theTsix promoter encompassing the DPXas34 locus leads to nonrandom inactivation of the mutant X, but it remains unresolved whether this phenotype is caused by loss of Tsixtranscription or by deletion of a crucial DNA element. In this study we determined the role of Tsix transcription in random X inactivation by using mouse embryonic stem (ES) cells as a model system. Two approaches were chosen to modulate Tsixtranscription with minimal disturbance of genomic sequences. First,Tsix transcription was functionally inhibited by introducing a transcriptional stop signal into the transcribed region of Tsix. In the second approach, an inducible system forTsix expression was created. We found that the truncation of the Tsix transcript led to complete nonrandom inactivation of the targeted X chromosome. Induction of Tsix transcription during ES cell differentiation, on the other hand, caused the targeted chromosome always to be chosen as the active chromosome. These results for the first time establish a function for antisense transcription in the regulation of X inactivation.
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Jacobson, Sandra, und Lorraine Pillus. „Molecular Requirements for Gene Expression Mediated by Targeted Histone Acetyltransferases“. Molecular and Cellular Biology 24, Nr. 13 (01.07.2004): 6029–39. http://dx.doi.org/10.1128/mcb.24.13.6029-6039.2004.
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ABSTRACT Histone acetyltransferases (HATs) play fundamental roles in regulating gene expression. HAT complexes with distinct subunit composition and substrate specificity act on chromatin-embedded genes with different promoter architecture and chromosomal locations. Because requirements for HAT complexes vary, a central question in transcriptional regulation is how different HAT complexes function in different chromosomal contexts. Here, we have tested the ability of targeted yeast HATs to regulate gene expression of an epigenetically silenced locus. Of a panel of HAT fusion proteins targeted to a telomeric reporter gene, Sas3p and Gcn5p selectively increased expression of the silenced gene. Reporter gene expression was not solely dependent on acetyltransferase activity of the targeted HAT. Further analysis of Gcn5p-mediated gene expression revealed collateral requirements for HAT complex subunits Spt8p and Spt3p, which interact with TATA-binding protein, and for a gene-specific transcription factor. These data demonstrate plasticity of gene expression mediated by HATs upon encountering novel promoter architecture and chromatin context. The telomeric location of the reporter gene used in these studies also provides insight into the molecular requirements for heterochromatin boundary formation and for overcoming transcriptional silencing.
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Shen, Hongtao, Jing Li, Xiujie Xie, Huan Yang, Mengxue Zhang, Bowen Wang, K. Craig Kent, Jorge Plutzky und Lian-Wang Guo. „BRD2 regulation of sigma-2 receptor upon cholesterol deprivation“. Life Science Alliance 4, Nr. 1 (24.11.2020): e201900540. http://dx.doi.org/10.26508/lsa.201900540.
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The sigma-2 receptor (S2R) has long been pharmacologically targeted for antipsychotic treatment and tumor imaging. Only recently was it known for its coding gene and for its role implicated in cholesterol homeostasis. Here, we have investigated the transcriptional control of S2R by the Bromo/ExtraTerminal epigenetic reader family (BETs, including BRD2, 3, and 4) upon cholesterol perturbation. Cholesterol deprivation was induced in ARPE19 cells using a blocker of lysosomal cholesterol export. This condition up-regulated S2R mRNA and protein, and also SREBP2 but not SREBP1, both transcription factors key to cholesterol/fatty acid metabolism. Silencing BRD2 but not BRD3 or BRD4 (though widely deemed a master regulator) averted S2R up-regulation that was induced by cholesterol deprivation. Silencing SREBP2 but not SREBP1 diminished S2R expression. Furthermore, endogenous BRD2 co-immunoprecipitated with the transcription-active N-terminal half of SREBP2, and chromatin immunoprecipitation-qPCR signified co-occupancy of BRD2, H3K27ac (histone acetylation), and SREBP2Nterm at the S2R gene promoter. In summary, this study reveals a previously unrecognized BRD2/SREBP2 cooperative regulation of S2R transcription, thus shedding new light on signaling in response to cholesterol deprivation.
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Wiggins, Amanda K., Guangwei Wei, Epaminondas Doxakis, Connie Wong, Amy A. Tang, Keling Zang, Esther J. Luo, Rachael L. Neve, Louis F. Reichardt und Eric J. Huang. „Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival“. Journal of Cell Biology 167, Nr. 2 (18.10.2004): 257–67. http://dx.doi.org/10.1083/jcb.200406131.
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The Pit1-Oct1-Unc86 domain (POU domain) transcription factor Brn3a controls sensory neuron survival by regulating the expression of Trk receptors and members of the Bcl-2 family. Loss of Brn3a leads to a dramatic increase in apoptosis and severe loss of neurons in sensory ganglia. Although recent evidence suggests that Brn3a-mediated transcription can be modified by additional cofactors, the exact mechanisms are not known. Here, we report that homeodomain interacting protein kinase 2 (HIPK2) is a pro-apoptotic transcriptional cofactor that suppresses Brn3a-mediated gene expression. HIPK2 interacts with Brn3a, promotes Brn3a binding to DNA, but suppresses Brn3a-dependent transcription of brn3a, trkA, and bcl-xL. Overexpression of HIPK2 induces apoptosis in cultured sensory neurons. Conversely, targeted deletion of HIPK2 leads to increased expression of Brn3a, TrkA, and Bcl-xL, reduced apoptosis and increases in neuron numbers in the trigeminal ganglion. Together, these data indicate that HIPK2, through regulation of Brn3a-dependent gene expression, is a critical component in the transcriptional machinery that controls sensory neuron survival.
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Osburn, Deborah L., Gang Shao, H. Martin Seidel und Ira G. Schulman. „Ligand-Dependent Degradation of Retinoid X Receptors Does Not Require Transcriptional Activity or Coactivator Interactions“. Molecular and Cellular Biology 21, Nr. 15 (01.08.2001): 4909–18. http://dx.doi.org/10.1128/mcb.21.15.4909-4918.2001.
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ABSTRACT Cells utilize ubiquitin-mediated proteolysis to regulate the activity of numerous proteins involved in signal transduction, cell cycle control, and transcriptional regulation. For a number of transcription factors, there appears to be a direct correlation between transcriptional activity and protein instability, suggesting that cells use targeted destruction as one method to down-regulate or attenuate gene expression. In this report we demonstrate that retinoid X receptors (RXRs) which function as versatile mediators of nuclear hormone-dependent gene expression are marked for destruction upon binding agonist ligands. Interestingly, when RXR serves as a heterodimeric partner for retinoic acid (RAR) or thyroid hormone (TR) receptors, binding of agonists by RAR or TR leads to degradation of both the transcriptionally active RAR or TR subunits as well as the transcriptionally inactive RXR subunit. Furthermore, using a series of mutants in the ligand-dependent activation domain (activation function 2), we demonstrate that agonist-stimulated degradation of RXR does not require corepressor release, coactivator binding, or transcriptional activity. Taken together, the data suggest a model for targeted destruction of transcription factors based on structural or conformational signals as opposed to functional coupling with gene transcription.
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Zhang, Xinyue, Jieyu Guo, Xiangxiang Wei, Cong Niu, Mengping Jia, Qinhan Li und Dan Meng. „Bach1: Function, Regulation, and Involvement in Disease“. Oxidative Medicine and Cellular Longevity 2018 (02.10.2018): 1–8. http://dx.doi.org/10.1155/2018/1347969.
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The transcription factor BTB and CNC homology 1 (Bach1) is widely expressed in most mammalian tissues and functions primarily as a transcriptional suppressor by heterodimerizing with small Maf proteins and binding to Maf recognition elements in the promoters of targeted genes. It has a key regulatory role in the production of reactive oxygen species, cell cycle, heme homeostasis, hematopoiesis, and immunity and has been shown to suppress ischemic angiogenesis and promote breast cancer metastasis. This review summarizes how Bach1 controls these and other cellular and physiological and pathological processes. Bach1 expression and function differ between different cell types. Thus, therapies designed to manipulate Bach1 expression will need to be tightly controlled and tailored for each specific disease state or cell type.
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Omelina, E. S., und A. V. Pindyurin. „Optogenetic regulation of endogenous gene transcription in mammals“. Vavilov Journal of Genetics and Breeding 23, Nr. 2 (30.03.2019): 219–25. http://dx.doi.org/10.18699/vj19.485.
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Despite the rapid development of approaches aimed to precisely control transcription of exogenous genes in time and space, design of systems providing similar tight regulation of endogenous gene expression is much more challenging. However, finding ways to control the activity of endogenous genes is absolutely necessary for further progress in safe and effective gene therapies and regenerative medicine. In addition, such systems are of particular interest for genetics, molecular and cell biology. An ideal system should ensure tunable and reversible spatio-temporal control over transcriptional activity of a gene of interest. Although there are drug-inducible systems for transcriptional regulation of endogenous genes, optogenetic approaches seem to be the most promising for the gene therapy applications, as they are noninvasive and do not exhibit toxicity in comparison with druginducible systems. Moreover, they are not dependent on chemical inducer diffusion rate or pharmacokinetics and exhibit fast activation-deactivation switching. Among optogenetic tools, long-wavelength light-controlled systems are more preferable for use in mammalian tissues in comparison with tools utilizing shorter wavelengths, since far-red/near-infrared light has the maximum penetration depth due to lower light scattering caused by lipids and reduced tissue autofluorescence at wavelengths above 700 nm. Here, we review such light-inducible systems, which are based on synthetic factors that can be targeted to any desired DNA sequence and provide activation or repression of a gene of interest. The factors include zinc finger proteins, transcription activator-like effectors (TALEs), and the CRISPR/Cas9 technology. We also discuss the advantages and disadvantages of these DNA targeting tools in the context of the light-inducible gene regulation systems.
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Shih, H. M., C. C. Chang, H. Y. Kuo und D. Y. Lin. „Daxx mediates SUMO-dependent transcriptional control and subnuclear compartmentalization“. Biochemical Society Transactions 35, Nr. 6 (23.11.2007): 1397–400. http://dx.doi.org/10.1042/bst0351397.
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SUMO (small ubiquitin-related modifier) modification is emerging as an important post-translational control in transcription. In general, SUMO modification is associated with transcriptional repression. Although many SUMO-modified transcription factors and co-activators have been identified, little is known about the mechanism underlying SUMOylation-elicited transcriptional repression. Here, we summarize that SUMO modification of transcription factors such as androgen receptor, glucocorticoid receptor, Smad4 and CBP [CREB (cAMP-response-element-binding protein)-binding protein] co-activator results in the recruitment of a transcriptional co-repressor Daxx, thereby causing transcriptional repression. Such a SUMO-dependent recruitment of Daxx is mediated by the interaction between the SUMO moiety of SUMOylated factors and Daxx SUMO-interacting motif. Interestingly, the transrepression effect of Daxx on these SUMOylated transcription factors can be relieved by SUMOylated PML (promyelocytic leukaemia) via altering Daxx partition from the targeted gene promoter to PML nuclear bodies. Because Daxx SUMO-interacting motif is a common binding site for SUMOylated factors, a model of competition for Daxx recruitment between SUMOylated PML and SUMOylated transcription factors was proposed. Together, our findings strongly suggest that Daxx functions as a SUMO reader in the SUMO-dependent regulation of transcription and subnuclear compartmentalization.
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Yu, Le, Ian J. Davis und Pengda Liu. „Regulation of EWSR1-FLI1 Function by Post-Transcriptional and Post-Translational Modifications“. Cancers 15, Nr. 2 (06.01.2023): 382. http://dx.doi.org/10.3390/cancers15020382.
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Ewing sarcoma is the second most common bone tumor in childhood and adolescence. Currently, first-line therapy includes multidrug chemotherapy with surgery and/or radiation. Although most patients initially respond to chemotherapy, recurrent tumors become treatment refractory. Pathologically, Ewing sarcoma consists of small round basophilic cells with prominent nuclei marked by expression of surface protein CD99. Genetically, Ewing sarcoma is driven by a fusion oncoprotein that results from one of a small number of chromosomal translocations composed of a FET gene and a gene encoding an ETS family transcription factor, with ~85% of tumors expressing the EWSR1::FLI1 fusion. EWSR1::FLI1 regulates transcription, splicing, genome instability and other cellular functions. Although a tumor-specific target, EWSR1::FLI1-targeted therapy has yet to be developed, largely due to insufficient understanding of EWSR1::FLI1 upstream and downstream signaling, and the challenges in targeting transcription factors with small molecules. In this review, we summarize the contemporary molecular understanding of Ewing sarcoma, and the post-transcriptional and post-translational regulatory mechanisms that control EWSR1::FLI1 function.
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Mauger, E., und P. H. Scott. „Mitogenic stimulation of transcription by RNA polymerase III“. Biochemical Society Transactions 32, Nr. 6 (26.10.2004): 976–77. http://dx.doi.org/10.1042/bst0320976.
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Regulation of protein synthesis is an important aspect of growth control. RNA polymerase (pol) III plays a key role in this process by catalysing production of tRNA and 5 S rRNA. Growth factors trigger a rapid increase in pol III activity and this is essential for cell proliferation. The transcription factor TFIIIB plays a key role in controlling pol III activity and is a target for regulation by a number of mechanisms. This review will focus on how TFIIIB is targeted by these proteins in response to mitogen stimulation.
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Chu, Wing-Keung, Li-Man Hung, Chun-Wei Hou und Jan-Kan Chen. „MicroRNA 630 Represses NANOG Expression through Transcriptional and Post-Transcriptional Regulation in Human Embryonal Carcinoma Cells“. International Journal of Molecular Sciences 23, Nr. 1 (21.12.2021): 46. http://dx.doi.org/10.3390/ijms23010046.
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The pluripotent transcription factor NANOG is essential for maintaining embryonic stem cells and driving tumorigenesis. We previously showed that PKC activity is involved in the regulation of NANOG expression. To explore the possible involvement of microRNAs in regulating the expression of key pluripotency factors, we performed a genome-wide analysis of microRNA expression in the embryonal carcinoma cell line NT2/D1 in the presence of the PKC activator, PMA. We found that MIR630 was significantly upregulated in PMA-treated cells. Experimentally, we showed that transfection of MIR630 mimic into embryonal carcinoma cell lines directly targeted the 3′UTR of OCT4, SOX2, and NANOG and markedly suppressed their expression. RNAhybrid and RNA22 algorithms were used to predict miRNA target sites in the NANOG 3′UTR, four possible target sites of MIR630 were identified. To examine the functional interaction between MIR630 and NANOG mRNA, the predicted MIR630 target sites in the NANOG 3′UTR were deleted and the activity of the reporters were compared. After targeted mutation of the predicted MIR630 target sites, the MIR630 mimic inhibited NANOG significantly less than the wild-type reporters. It is worth noting that mutation of a single putative binding site in the 3′UTR of NANOG did not completely abolish MIR630-mediated suppression, suggesting that MIR630 in the NANOG 3′UTR may have multiple binding sites and act together to maximally repress NANOG expression. Interestingly, MIR630 mimics significantly downregulated NANOG gene transcription. Exogenous expression of OCT4, SOX2, and NANOG lacking the 3′UTR almost completely rescued the reduced transcriptional activity of MIR630. MIR630 mediated the expression of differentiation markers in NT2/D1 cells, suggesting that MIR630 leads to the differentiation of NT2/D1 cell. Our findings show that MIR630 represses NANOG through transcriptional and post-transcriptional regulation, suggesting a direct link between core pluripotency factors and MIR630.
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Pitts, Stephanie, und Marikki Laiho. „Regulation of RNA Polymerase I Stability and Function“. Cancers 14, Nr. 23 (24.11.2022): 5776. http://dx.doi.org/10.3390/cancers14235776.
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RNA polymerase I is a highly processive enzyme with fast initiation and elongation rates. The structure of Pol I, with its in-built RNA cleavage ability and incorporation of subunits homologous to transcription factors, enables it to quickly and efficiently synthesize the enormous amount of rRNA required for ribosome biogenesis. Each step of Pol I transcription is carefully controlled. However, cancers have highjacked these control points to switch the enzyme, and its transcription, on permanently. While this provides an exceptional benefit to cancer cells, it also creates a potential cancer therapeutic vulnerability. We review the current research on the regulation of Pol I transcription, and we discuss chemical biology efforts to develop new targeted agents against this process. Lastly, we highlight challenges that have arisen from the introduction of agents with promiscuous mechanisms of action and provide examples of agents with specificity and selectivity against Pol I.
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Brown, Jay C. „Role of Polycomb Repressive Complex 2 in Regulation of Human Transcription Factor Gene Expression“. Genetics & Genomic Sciences 7, Nr. 1 (01.08.2022): 1–30. http://dx.doi.org/10.24966/ggs-2485/100033.
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For instance, this was the case with 16 of 20 TF families. The results are interpreted to indicate that while individual TFs such as EZH2 may be specific for broadly expressed or tissue targeted genes, this is not a property of most TF families. Most have both broadly expressed and tissue targeted members
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Sayed, Mohammed, und Juw Won Park. „miRinGO: Prediction of Biological Processes Indirectly Targeted by Human microRNAs“. Non-Coding RNA 9, Nr. 1 (22.01.2023): 11. http://dx.doi.org/10.3390/ncrna9010011.
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MicroRNAs (miRNAs) are small non-coding RNAs that are known for their role in the post-transcriptional regulation of target genes. Typically, their functions are predicted by first identifying their target genes and then finding biological processes enriched in these targets. Current tools for miRNA functional analysis use only genes with physical binding sites as their targets and exclude other genes that are indirectly targeted transcriptionally through transcription factors. Here, we introduce a method to predict gene ontology (GO) annotations indirectly targeted by microRNAs. The proposed method resulted in better performance in predicting known miRNA-GO term associations compared to the canonical approach. To facilitate miRNA GO enrichment analysis, we developed an R Shiny application, miRinGO, that is freely available online at GitHub.
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Engel, Anja J., Laura-Marie Winterstein, Marina Kithil, Markus Langhans, Anna Moroni und Gerhard Thiel. „Light-Regulated Transcription of a Mitochondrial-Targeted K+ Channel“. Cells 9, Nr. 11 (19.11.2020): 2507. http://dx.doi.org/10.3390/cells9112507.
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The inner membranes of mitochondria contain several types of K+ channels, which modulate the membrane potential of the organelle and contribute in this way to cytoprotection and the regulation of cell death. To better study the causal relationship between K+ channel activity and physiological changes, we developed an optogenetic platform for a light-triggered modulation of K+ conductance in mitochondria. By using the light-sensitive interaction between cryptochrome 2 and the regulatory protein CIB1, we can trigger the transcription of a small and highly selective K+ channel, which is in mammalian cells targeted into the inner membrane of mitochondria. After exposing cells to very low intensities (≤0.16 mW/mm2) of blue light, the channel protein is detectable as an accumulation of its green fluorescent protein (GFP) tag in the mitochondria less than 1 h after stimulation. This system allows for an in vivo monitoring of crucial physiological parameters of mitochondria, showing that the presence of an active K+ channel causes a substantial depolarization compatible with the effect of an uncoupler. Elevated K+ conductance also results in a decrease in the Ca2+ concentration in the mitochondria but has no impact on apoptosis.
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Janostiak, Radoslav, Ariadna Torres-Sanchez, Francesc Posas und Eulàlia de Nadal. „Understanding Retinoblastoma Post-Translational Regulation for the Design of Targeted Cancer Therapies“. Cancers 14, Nr. 5 (28.02.2022): 1265. http://dx.doi.org/10.3390/cancers14051265.
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The retinoblastoma protein (Rb1) is a prototypical tumor suppressor protein whose role was described more than 40 years ago. Together with p107 (also known as RBL1) and p130 (also known as RBL2), the Rb1 belongs to a family of structurally and functionally similar proteins that inhibits cell cycle progression. Given the central role of Rb1 in regulating proliferation, its expression or function is altered in most types of cancer. One of the mechanisms underlying Rb-mediated cell cycle inhibition is the binding and repression of E2F transcription factors, and these processes are dependent on Rb1 phosphorylation status. However, recent work shows that Rb1 is a convergent point of many pathways and thus the regulation of its function through post-translational modifications is more complex than initially expected. Moreover, depending on the context, downstream signaling can be both E2F-dependent and -independent. This review seeks to summarize the most recent research on Rb1 function and regulation and discuss potential avenues for the design of novel cancer therapies.
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Kwon, Geunho, und Kyuho Kang. „Transcriptional regulation of IL10 gene in human macrophages“. Journal of Immunology 204, Nr. 1_Supplement (01.05.2020): 152.21. http://dx.doi.org/10.4049/jimmunol.204.supp.152.21.
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Abstract IL-10 is an anti-inflammatory cytokine with a crucial role in immune homeostasis. Dysregulated production of IL-10 has been linked to certain autoimmune and inflammatory diseases. IL-10 is strongly induced by TLR ligands and suppressed by IFN-γ as part of the synergistic activation of inflammatory genes. However, the molecular mechanisms that regulate expression of the IL10 gene, especially in human macrophages, are incompletely understood. By using epigenomic analysis of ATAC-seq and ChIP-seq analysis we have identified human macrophage-specific enhancers in the IL10 gene locus. In these putative enhancers, we observed that chromatin accessibility and histone acetylation are increased by LPS stimulation. We also found that p300 was frequently recruited to these macrophage-specific cis-regulatory elements (CREs) in LPS-stimulated macrophages. One of these potential LPS-induced enhancers, CRE+6, is located 6kb upstream of the IL10 transcriptional start site and contains transcription factor binding motifs and autoimmune disease-associated SNPs. CRE+6 showed constitutive binding of the macrophage-lineage-determining factor PU.1 and LPS-inducible binding of AP-1 and STAT3. LPS stimulation increased eRNA transcription from CRE+6. The functional relevance of CRE+6 eRNA was confirmed by eRNA-targeted knockdown experiments. Strikingly, the mechanism by which IFN-γ suppresses IL10 expression appeared to be decommissioning of enhancers, as IFN-γ strongly suppressed TLR-induced positive enhancer marks and eRNA transcription. Our study implicates that crucial enhancer elements cooperate with the core promoter in LPS- and IFN-γ-mediated regulation of IL-10 gene transcription in human macrophages.
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Pham, Lan V., Archito T. Tamayo, Changping Li, Carlos Bueso-Ramos und Richard J. Ford. „An epigenetic chromatin remodeling role for NFATc1 in transcriptional regulation of growth and survival genes in diffuse large B-cell lymphomas“. Blood 116, Nr. 19 (11.11.2010): 3899–906. http://dx.doi.org/10.1182/blood-2009-12-257378.
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Abstract The nuclear factor of activated T cells (NFAT) family of transcription factors functions as integrators of multiple signaling pathways by binding to chromatin in combination with other transcription factors and coactivators to regulate genes central for cell growth and survival in hematopoietic cells. Recent experimental evidence has implicated the calcineurin/NFAT signaling pathway in the pathogenesis of various malignancies, including diffuse large B-cell lymphoma (DLBCL). However, the molecular mechanism(s) underlying NFATc1 regulation of genes controlling lymphoma cell growth and survival is still unclear. In this study, we demonstrate that the transcription factor NFATc1 regulates gene expression in DLBCL cells through a chromatin remodeling mechanism that involves recruitment of the SWItch/Sucrose NonFermentable chromatin remodeling complex ATPase enzyme SMARCA4 (also known as Brahma-related gene 1) to NFATc1 targeted gene promoters. The NFATc1/Brahma-related gene 1 complex induces promoter DNase I hypersensitive sites and recruits other transcription factors to the active chromatin site to regulate gene transcription. Targeting NFATc1 with specific small hairpin RNA inhibits DNase I hypersensitive site formation and down-regulates target gene expression. Our data support a novel epigenetic control mechanism for the transcriptional regulation of growth and survival genes by NFATc1 in the pathophysiology of DLBCL and suggests that targeting NFATc1 could potentially have therapeutic value.
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Calero-Nieto, Fernando, Antonio Di Pietro, M. Isabel G. Roncero und Concepcion Hera. „Role of the Transcriptional Activator XlnR of Fusarium oxysporum in Regulation of Xylanase Genes and Virulence“. Molecular Plant-Microbe Interactions® 20, Nr. 8 (August 2007): 977–85. http://dx.doi.org/10.1094/mpmi-20-8-0977.
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Fungal infection of plants involves degradation of the host cell wall through the action of lytic enzymes secreted by the pathogen. The role of these enzymes in virulence is difficult to determine due to their functional redundancy and, therefore, remains controversial. Here, we have studied XlnR, a zinc-finger transcription factor from the vascular wilt pathogen Fusarium oxysporum that is orthologous to the major transcriptional activator of xylanase genes in Aspergillus spp. Transcription of the xlnR gene was activated by inducing carbon sources such as oat spelt xylan (OSX) and repressed by glucose. Targeted knockout of xlnR in F. oxysporum resulted in lack of transcriptional activation of structural xylanase genes, both in culture and during infection of tomato plants, as well as in dramatically reduced extracellular xylanase activity. By contrast, overexpression of xlnR under the control of the Aspergillus nidulans gpdA promoter did not significantly increase xylanase activity, suggesting that XlnR is regulated not only at the transcriptional but also at the post-translational level. The ΔxlnR mutants were still fully virulent on tomato plants. Thus, XlnR, the major transcriptional activator of xylanase genes, is not an essential virulence determinant in F. oxysporum.
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Gong, Zehao, Yingqing Luo, Wenfa Zhang, Wei Jian, Lu Zhang, Xueli Gao, Xiaowei Hu et al. „A SlMYB75-centred transcriptional cascade regulates trichome formation and sesquiterpene accumulation in tomato“. Journal of Experimental Botany 72, Nr. 10 (23.02.2021): 3806–20. http://dx.doi.org/10.1093/jxb/erab086.
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Abstract Tomato trichomes act as a mechanical and chemical barrier against pests. An R2R3 MYB transcription factor gene, SlMYB75, is highly expressed in type II, V, and VI trichomes. SlMYB75 protein is located in the nucleus and possesses transcriptional activation activity. Down-regulation of SlMYB75 increased the formation of type II, V, and VI trichomes, accumulation of δ-elemene, β-caryophyllene, and α-humulene in glandular trichomes, and tolerance to spider mites in tomato. In contrast, overexpression of SlMYB75 inhibited trichome formation and sesquiterpene accumulation, and increased plant sensitivity to spider mites. RNA-Seq analyses of the SlMYB75 RNAi line indicated massive perturbation of the transcriptome, with a significant impact on several classes of transcription factors. Expression of the MYB genes SlMYB52 and SlTHM1 was strongly reduced in the RNAi line and increased in the SlMYB75-overexpressing line. SlMYB75 protein interacted with SlMYB52 and SlTHM1 and activated their expression. SlMYB75 directly targeted the promoter of the cyclin gene SlCycB2, increasing its activity. The auxin response factor SlARF4 directly targeted the promoter of SlMYB75 and inhibited its expression. SlMYB75 also bound to the promoters of the terpene synthase genes SlTPS12, SlTPS31, and SlTPS35, inhibiting their transcription. Our findings indicate that SlMYB75 perturbation affects several transcriptional circuits, resulting in altered trichome density and metabolic content.
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Lee, Sung Kuk, Jack D. Newman und Jay D. Keasling. „Catabolite Repression of the Propionate Catabolic Genes in Escherichia coli and Salmonella enterica: Evidence for Involvement of the Cyclic AMP Receptor Protein“. Journal of Bacteriology 187, Nr. 8 (15.04.2005): 2793–800. http://dx.doi.org/10.1128/jb.187.8.2793-2800.2005.
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ABSTRACT Previous studies with Salmonella enterica serovar Typhimurium LT2 demonstrated that transcriptional activation of the prpBCDE operon requires the function of transcription factor PrpR, sigma-54, and IHF. In this study, we found that transcription from the prpBCDE and prpR promoters was down-regulated by the addition of glucose or glycerol, indicating that these genes may be regulated by the cyclic AMP (cAMP)-cAMP receptor protein (CRP) complex. Targeted mutagenesis of a putative CRP-binding site in the promoter region between prpR and prpBCDE suggested that these genes are under the control of CRP. Furthermore, cells with defects in cya or crp exhibited reduced transcriptional activation of prpR and prpBCDE in Escherichia coli. These results demonstrate that propionate metabolism is subject to catabolite repression by the global transcriptional regulator CRP and that this regulation is effected through control of both the regulator gene prpR and the prpBCDE operon itself. The unique properties of the regulation of these two divergent promoters may have important implications for mechanisms of CRP-dependent catabolite repression acting in conjunction with a member of the sigma-54 family of transcriptional activators.
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Block, Gregory J., Christopher H. Eskiw, Graham Dellaire und David P. Bazett-Jones. „Transcriptional Regulation Is Affected by Subnuclear Targeting of Reporter Plasmids to PML Nuclear Bodies“. Molecular and Cellular Biology 26, Nr. 23 (11.09.2006): 8814–25. http://dx.doi.org/10.1128/mcb.00636-06.
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ABSTRACT Whereas the PML protein has been reported to have both transcriptional coactivator and corepressor potential, the contribution of the PML nuclear body (PML NB) itself to transcriptional regulation is not well understood. Here we demonstrate that plasmid DNA artificially tethered to PML or the PML NB-targeting domain of Sp100 is preferentially localized to PML NBs. Using the tethering technique, we targeted a simian virus 40 promoter-driven luciferase reporter plasmid to PML NBs, resulting in the repression of the transgene transcriptional activity. Conversely, the tethering of a cytomegalovirus promoter-containing reporter plasmid resulted in activation. Targeting a minimal eukaryotic promoter did not affect its activity. The expression of targeted promoters could be modulated by altering the cellular concentration of PML NB components, including Sp100 and isoforms of the PML protein. Finally, we demonstrate that ICP0, the promiscuous herpes simplex virus transactivator, increases the level of transcriptional activation of plasmid DNA tethered to the PML NB. We conclude that when PML NB components are artificially tethered to reporter plasmids, the PML NB contributes to the regulation of the tethered DNA in a promoter-dependent manner. Our findings demonstrate that transient transcription assays are sensitive to the subnuclear localization of the transgene plasmid.
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Bowman, Tamara A., Madeline M. Wong, Linda K. Cox, Joseph J. Baldassare und John C. Chrivia. „Loss of H2A.Z Is Not Sufficient to Determine Transcriptional Activity of Snf2-Related CBP Activator Protein or p400 Complexes“. International Journal of Cell Biology 2011 (2011): 1–8. http://dx.doi.org/10.1155/2011/715642.
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The p400 and SRCAP (Snf2-related CBP activator protein) complexes remodel chromatin by catalyzing deposition of histone H2A.Z into nucleosomes. This remodeling activity has been proposed as a basis for regulation of transcription by these complexes. Transcript levels ofp21orSp1mRNAs after knockdown of p400 or SRCAP reveals that each regulates transcription of these promoters differently. In this study, we asked whether deposition of H2A.Z within specific nucleosomes by p400 or SRCAP dictates transcriptional activity. Our data indicates that nucleosome density at specificp21orSp1promoter positions is not altered by the loss of either remodeling complex. However, knockdown of SRCAP or p400 reduces deposition of H2A.Z∼50% into allp21andSp1promoter nucleosomes. Thus, H2A.Z deposition is not targeted to specific nucleosomes. These results indicate that the deposition of H2A.Z by the p400 or SRCAP complexes is not sufficient to determine how each regulates transcription. This conclusion is further supported by studies that demonstrate a SRCAPΔATPmutant unable to deposit H2A.Z has similar transcriptional activity as wild-type SRCAP.
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Landeira, David, und Miguel Navarro. „Nuclear repositioning of the VSG promoter during developmental silencing in Trypanosoma brucei“. Journal of Cell Biology 176, Nr. 2 (08.01.2007): 133–39. http://dx.doi.org/10.1083/jcb.200607174.
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Interphase nuclear repositioning of chromosomes has been implicated in the epigenetic regulation of RNA polymerase (pol) II transcription. However, little is known about the nuclear position–dependent regulation of RNA pol I–transcribed loci. Trypanosoma brucei is an excellent model system to address this question because its two main surface protein genes, procyclin and variant surface glycoprotein (VSG), are transcribed by pol I and undergo distinct transcriptional activation or downregulation events during developmental differentiation. Although the monoallelically expressed VSG locus is exclusively localized to an extranucleolar body in the bloodstream form, in this study, we report that nonmutually exclusive procyclin genes are located at the nucleolar periphery. Interestingly, ribosomal DNA loci and pol I transcription activity are restricted to similar perinucleolar positions. Upon developmental transcriptional downregulation, however, the active VSG promoter selectively undergoes a rapid and dramatic repositioning to the nuclear envelope. Subsequently, the VSG promoter region was subjected to chromatin condensation. We propose a model whereby the VSG expression site pol I promoter is selectively targeted by temporal nuclear repositioning during developmental silencing.
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McAninch, Dale, Ella P. Thomson und Paul Q. Thomas. „Genome-wide DNA-binding profile of SRY-box transcription factor 3 (SOX3) in mouse testes“. Reproduction, Fertility and Development 32, Nr. 16 (2020): 1260. http://dx.doi.org/10.1071/rd20108.
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Spermatogenesis is the male version of gametogenesis, where germ cells are transformed into haploid spermatozoa through a tightly controlled series of mitosis, meiosis and differentiation. This process is reliant on precisely timed changes in gene expression controlled by several different hormonal and transcriptional mechanisms. One important transcription factor is SRY-box transcription factor 3 (SOX3), which is transiently expressed within the uncommitted spermatogonial stem cell population. Sox3-null mouse testes exhibit a block in spermatogenesis, leading to infertility or subfertility. However, the molecular role of SOX3 during spermatogonial differentiation remains poorly understood because the genomic regions targeted by this transcription factor have not been identified. In this study we used chromatin immunoprecipitation sequencing to identify and characterise the endogenous genome-wide binding profile of SOX3 in mouse testes at Postnatal Day 7. We show that neurogenin3 (Neurog3 or Ngn3) is directly targeted by SOX3 in spermatogonial stem cells via a novel testes-specific binding site. We also implicate SOX3, for the first time, in direct regulation of histone gene expression and demonstrate that this function is shared by both neural progenitors and testes, and with another important transcription factor required for spermatogenesis, namely promyelocytic leukaemia zinc-finger (PLZF). Together, these data provide new insights into the function of SOX3 in different stem cell contexts.
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Bolger, Steven J., Patricia A. Gonzales Hurtado, Jason D. Hoffert, Fahad Saeed, Trairak Pisitkun und Mark A. Knepper. „Quantitative phosphoproteomics in nuclei of vasopressin-sensitive renal collecting duct cells“. American Journal of Physiology-Cell Physiology 303, Nr. 10 (15.11.2012): C1006—C1020. http://dx.doi.org/10.1152/ajpcell.00260.2012.
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Vasopressin regulates transport across the collecting duct epithelium in part via effects on gene transcription. Transcriptional regulation occurs partially via changes in phosphorylation of transcription factors, transcriptional coactivators, and protein kinases in the nucleus. To test whether vasopressin alters the nuclear phosphoproteome of vasopressin-sensitive cultured mouse mpkCCD cells, we used stable isotope labeling and mass spectrometry to quantify thousands of phosphorylation sites in nuclear extracts and nuclear pellet fractions. Measurements were made in the presence and absence of the vasopressin analog dDAVP. Of the 1,251 sites quantified, 39 changed significantly in response to dDAVP. Network analysis of the regulated proteins revealed two major clusters (“cell-cell adhesion” and “transcriptional regulation”) that were connected to known elements of the vasopressin signaling pathway. The hub proteins for these two clusters were the transcriptional coactivator β-catenin and the transcription factor c-Jun. Phosphorylation of β-catenin at Ser552 was increased by dDAVP [log2(dDAVP/vehicle) = 1.79], and phosphorylation of c-Jun at Ser73 was decreased [log2(dDAVP/vehicle) = −0.53]. The β-catenin site is known to be targeted by either protein kinase A or Akt, both of which are activated in response to vasopressin. The c-Jun site is a canonical target for the MAP kinase Jnk2, which is downregulated in response to vasopressin in the collecting duct. The data support the idea that vasopressin-mediated control of transcription in collecting duct cells involves selective changes in the nuclear phosphoproteome. All data are available to users at http://helixweb.nih.gov/ESBL/Database/mNPPD/ .
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Doak, Andrea E., Rose Qu und Kevin J. Cheung. „Abstract A014: Transcriptional regulation of basal leader cell identity during collective breast cancer invasion“. Cancer Research 83, Nr. 2_Supplement_2 (15.01.2023): A014. http://dx.doi.org/10.1158/1538-7445.metastasis22-a014.
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Abstract An early step in breast cancer progression is invasion of tumor cells into surrounding tissues. In many breast cancers, particularly ductal carcinomas, this invasion is accomplished by tumor cells migrating as a cohesive group. This often involves cells that take on heterogeneous roles as either leader or follower cells. Studies in common mouse and human breast cancer models have established that leader cells express high levels of keratin-14 (K14) and other basal epithelial markers. The presence of these K14+ cells promote metastasis and predict poor prognosis. The molecular mechanisms regulating K14+ leader cell identity and the methods for targeted depletion of these cells remain obscure. Here we performed time-sampled single cell RNA-sequencing in 3D type I collagen-embedded tumor organoids isolated from the MMTV-PyMT luminal B model of breast cancer. 11 distinct cellular transcriptional states were identified, and through correlation with K14 expression and invasive strand formation we classified one of the states as leader cells. Having confirmed the leader cell cluster markers spatially localize to the invasive front, we next asked which transcription factors were enriched, reasoning that transcription factors could be master regulators of leader cell fate. Three different shRNAs targeting ten genes were systematically evaluated for their effects on collective invasion and keratin-14 transcription. Each transcription factor was designated as either an invasion promoter or invasion suppressor depending on the correlation between transcription factor expression and organoid invasion. Studies are ongoing investigating the impact of invasion-promoting and invasion-suppressing transcription factors on cellular transcriptional states and metastatic dissemination in-vivo. We propose that targeting invasion-suppressing pathways could be combined with therapies that specifically target and eliminate K14+ invasive cells. To this end, we have identified multiple candidate druggable targets and specific surface markers expressed in K14+ invasive cells. Citation Format: Andrea E. Doak, Rose Qu, Kevin J. Cheung. Transcriptional regulation of basal leader cell identity during collective breast cancer invasion [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A014.
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Xu, Tao, Yongchao Li, Joy D. Van Nostrand, Zhili He und Jizhong Zhou. „Cas9-Based Tools for Targeted Genome Editing and Transcriptional Control“. Applied and Environmental Microbiology 80, Nr. 5 (03.01.2014): 1544–52. http://dx.doi.org/10.1128/aem.03786-13.
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ABSTRACTDevelopment of tools for targeted genome editing and regulation of gene expression has significantly expanded our ability to elucidate the mechanisms of interesting biological phenomena and to engineer desirable biological systems. Recent rapid progress in the study of a clustered, regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) protein system in bacteria has facilitated the development of newly facile and programmable platforms for genome editing and transcriptional control in a sequence-specific manner. The core RNA-guided Cas9 endonuclease in the type II CRISPR system has been harnessed to realize gene mutation and DNA deletion and insertion, as well as transcriptional activation and repression, with multiplex targeting ability, just by customizing 20-nucleotide RNA components. Here we describe the molecular basis of the type II CRISPR/Cas system and summarize applications and factors affecting its utilization in model organisms. We also discuss the advantages and disadvantages of Cas9-based tools in comparison with widely used customizable tools, such as Zinc finger nucleases and transcription activator-like effector nucleases.
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Nekhai, Sergei, Michael Petukhov und Denitra Breuer. „Regulation of CDK9 Activity by Phosphorylation and Dephosphorylation“. BioMed Research International 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/964964.
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HIV-1 transcription is regulated by CDK9/cyclin T1, which, unlike a typical cell cycle-dependent kinase, is regulated by associating with 7SK small nuclear ribonuclear protein complex (snRNP). While the protein components of this complex are well studied, the mechanism of the complex formation is still not fully understood. The association of CDK9/cyclin T1 with 7SK snRNP is, in part, regulated by a reversible CDK9 phosphorylation. Here, we present a comprehensive review of the kinases and phosphatases involved in CDK9 phosphorylation and discuss their role in regulation of HIV-1 replication and potential for being targeted for drug development. We propose a novel pathway of HIV-1 transcription regulation via CDK9 Ser-90 phosphorylation by CDK2 and CDK9 Ser-175 dephosphorylation by protein phosphatase-1.
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Nylén, Carolina, Wataru Aoi, Ahmed M. Abdelmoez, David G. Lassiter, Leonidas S. Lundell, Harriet Wallberg-Henriksson, Erik Näslund, Nicolas J. Pillon und Anna Krook. „IL6 and LIF mRNA expression in skeletal muscle is regulated by AMPK and the transcription factors NFYC, ZBTB14, and SP1“. American Journal of Physiology-Endocrinology and Metabolism 315, Nr. 5 (01.11.2018): E995—E1004. http://dx.doi.org/10.1152/ajpendo.00398.2017.
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Adenosine monophosphate-activated protein kinase (AMPK) controls glucose and lipid metabolism and modulates inflammatory responses to maintain metabolic and inflammatory homeostasis during low cellular energy levels. The AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) interferes with inflammatory pathways in skeletal muscle, but the mechanisms are undefined. We hypothesized that AMPK activation reduces cytokine mRNA levels by blocking transcription through one or several transcription factors. Three skeletal muscle models were used to study AMPK effects on cytokine mRNA: human skeletal muscle strips obtained from healthy men incubated in vitro, primary human muscle cells, and rat L6 cells. In all three skeletal muscle systems, AICAR acutely reduced cytokine mRNA levels. In L6 myotubes treated with the transcriptional blocker actinomycin D, AICAR addition did not further reduce Il6 or leukemia inhibitory factor ( Lif) mRNA, suggesting that AICAR modulates cytokine expression through regulating transcription rather than mRNA stability. A cross-species bioinformatic approach identified novel transcription factors that may regulate LIF and IL6 mRNA. The involvement of these transcription factors was studied after targeted gene-silencing by siRNA. siRNA silencing of the transcription factors nuclear transcription factor Y subunit c ( Nfyc), specificity protein 1 ( Sp1), and zinc finger and BTB domain containing 14 ( Zbtb14), or AMPK α1/α2 subunits, increased constitutive levels of Il6 and Lif. Our results identify novel candidates in the regulation of skeletal muscle cytokine expression and identify AMPK, Nfyc, Sp1, and Zbtb14 as novel regulators of immunometabolic signals from skeletal muscle.