In the United States, prostate cancer is the second leading cause of cancer-related deaths among men with an approximately 220,000 patients diagnosed with the disease in 2015. Prostate cancer is a hormone-driven tumor, a...In the United States, prostate cancer is the second leading cause of cancer-related deaths among men with an approximately 220,000 patients diagnosed with the disease in 2015. Prostate cancer is a hormone-driven tumor, and a common therapy is androgen-deprivation therapy (ADT) that involves anti-androgen treatments and/or castration therapy. Understanding the molecular basis for androgen-independent tumors is crucial toward developing new therapies for these patients. Understanding how androgen receptor itself functions is an important step in elucidating this process. Androgen receptor (AR), NR3C4, is a nuclear hormone receptor and functions as a DNA-binding transcription factor that regulates the expression of protein-coding genes. Translocation of AR to improper gene promoter elements or DNA-binding sites can result in an alteration in gene expression and thus normal prostate function. Therefore, it is crucial to understand which AR-promoter interactions are drivers of disease, as compared to promiscuous or benign AR-binding interactions. While a large portion of our genome is considered a gene desert, it is now appreciated that these regions of the genome contain non-coding RNA genes such as microRNAs (miRNAs). These non-coding RNAs have enormous regulatory potential, as they post-transcriptionally regulate gene expression by binding to messenger RNAs (mRNAs) to promote degradation or intervention of translational processes. In this review, we focus specifically on the notion that mis-regulation of non-coding RNAs such as miRNAs by improper AR-DNA binding are an important component that promotes prostate cancer. We also highlight the role of miR-206 and the interaction of miR-206 and AR within this process, given this is a miRNA known to be regulated by hormones in both breast and prostate cancer.
Type 3 RNA polymerase III (Pol III) promoters are widely used for the expression of small RNAs such as short hairpin RNA and guide RNA in the popular RNAi and CRISPR-Cas gene regulation systems. Although it is generally...Type 3 RNA polymerase III (Pol III) promoters are widely used for the expression of small RNAs such as short hairpin RNA and guide RNA in the popular RNAi and CRISPR-Cas gene regulation systems. Although it is generally believed that type 3 Pol III promoters use a defined transcription start site (+1 position), most man-made promoter constructs contain local sequence alterations of which the impact on transcription efficiency and initiation accuracy is not known. For three human type 3 Pol III promoters (7SK, U6, and H1), we demonstrated that the nucleotides around the +1 position affect both the transcriptional efficiency and start site selection. Human 7SK and U6 promoters with A or G at the +1 position efficiently produced small RNAs with a precise +1 start site. The human H1 promoter with +1A or G also efficiently produced small RNAs but from multiple start sites in the -3/-1 window. These results provide new insights for the design of vectors for accurate expression of designed small RNAs for research and therapeutic purposes.
Vockley CM, McDowell IC, D'Ippolito AM
… +1 more, Reddy TE
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· 2017 Aug · PMID 28598247
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Gene regulation is fundamentally important for the coordination of diverse biologic processes including homeostasis and responses to developmental and environmental stimuli. Transcription factor (TF) binding sites are on...Gene regulation is fundamentally important for the coordination of diverse biologic processes including homeostasis and responses to developmental and environmental stimuli. Transcription factor (TF) binding sites are one of the major functional subunits of gene regulation. They are arranged in cis-regulatory modules (CRMs) that can be more active than the sum of their individual effects. Recently, we described a mechanism of glucocorticoid (GC)-induced gene regulation in which the glucocorticoid receptor (GR) binds coordinately to multiple CRMs that are 10s of kilobases apart in the genome. In those results, the minority of GR binding sites appear to involve direct TF:DNA interactions. Meanwhile, other GR binding sites in a cluster interact with those direct binding sites to tune their gene regulatory activity. Here, we consider the implications of those and related results in the context of existing models of gene regulation. Based on our analyses, we propose that the billboard and regulatory grammar models of cis-regulatory element activity be expanded to consider the influence of long-range interactions between cis-regulatory modules.
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· 2017 Aug · PMID 28548879
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Transcriptional control is critical in relaying signals mediated by Ras and Rho family small GTPases to effect gene expression. In the classical model, signaling components such as MAP kinase target sequence-specific tra...Transcriptional control is critical in relaying signals mediated by Ras and Rho family small GTPases to effect gene expression. In the classical model, signaling components such as MAP kinase target sequence-specific transcription factors, which in turn recruit RNA polymerase (Pol) II holoenzyme to the promoter and activate transcription. Findings in recent years have led to the proposal of a shortcut model in which the Mediator components of the Pol II holoenzyme are regulated by signaling pathways. A very recent finding shows that an evolutionarily conserved Rho GTPase signaling pathway can directly modulate the Pol II C-terminal domain (CTD) phosphorylation by inhibiting the CTD phosphatase in yeast and Arabidopsis. This shortcut model allows direct targeting of the Pol II CTD code and thus has an advantage over the classical model in bringing about rapid, large-scale changes in gene expression.
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· 2017 Mar · PMID 28453430
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Recently, we reported the unexpected finding that the monoubiquitination of histone H2B (H2Bub1) regulates inducible enhancers. Here, we propose a conceptual framework to reconcile the apparently discrepant roles of H2Bu...Recently, we reported the unexpected finding that the monoubiquitination of histone H2B (H2Bub1) regulates inducible enhancers. Here, we propose a conceptual framework to reconcile the apparently discrepant roles of H2Bub1 in transcription initiation and elongation, and we discuss how H2Bub1 could regulate cellular processes linked to non-coding transcription.
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· 2017 Aug · PMID 28448767
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In Saccharomyces cerevisiae, a group of more than 200 co-regulated genes (Ribi genes) is involved in ribosome biogenesis. This regulon has recently been shown to rely on a small set of transcriptional regulators (mainly...In Saccharomyces cerevisiae, a group of more than 200 co-regulated genes (Ribi genes) is involved in ribosome biogenesis. This regulon has recently been shown to rely on a small set of transcriptional regulators (mainly Abf1, but also Reb1, Tbf1 and Rap1) previously referred to as general regulatory factors (GRFs) because of their widespread binding and action at many promoters and other specialized genomic regions. Intriguingly, Abf1 binding to Ribi genes is differentially modulated in response to distinct nutrition signaling pathways. Such a dynamic promoter association has the potential to orchestrate both activation and repression of Ribi genes in synergy with neighboring regulatory sites and through the functional interplay of histone acetyltransferases and deacetylases.
Rosonina E, Akhter A, Dou Y
… +2 more, Babu J, Sri Theivakadadcham VS
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· 2017 Aug · PMID 28379052
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Transcription factors (TFs) are among the most frequently detected targets of sumoylation, and effects of the modification have been studied for about 200 individual TFs to date. TF sumoylation is most often associated w...Transcription factors (TFs) are among the most frequently detected targets of sumoylation, and effects of the modification have been studied for about 200 individual TFs to date. TF sumoylation is most often associated with reduced target gene expression, which can be mediated by enhanced interactions with corepressors or by interference with protein modifications that promote transcription. However, recent studies show that sumoylation also regulates gene expression by controlling the levels of TFs that are associated with chromatin. SUMO can mediate this by modulating TF DNA-binding activity, promoting clearance of TFs from chromatin, or indirectly, by influencing TF abundance or localization.
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· 2017 May · PMID 28340332
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Early work on the control of transcription of the human immunodeficiency virus (HIV) laid the foundation for our current knowledge of how RNA Polymerase II is released from promoter-proximal pausing sites and transcripti...Early work on the control of transcription of the human immunodeficiency virus (HIV) laid the foundation for our current knowledge of how RNA Polymerase II is released from promoter-proximal pausing sites and transcription elongation is enhanced. The viral Tat activator recruits Positive Transcription Elongation Factor b (P-TEFb) and Super Elongation Complex (SEC) that jointly drive transcription elongation. While substantial progress in understanding the role of SEC in HIV gene transcription elongation has been obtained, defining of the mechanisms that govern SEC functions is still limited, and the role of SEC in controlling HIV transcription in the absence of Tat is less clear. Here we revisit the contribution of SEC in early steps of HIV gene transcription. In the absence of Tat, the AF4/FMR2 Family member 4 (AFF4) of SEC efficiently activates HIV transcription, while gene activation by its homolog AFF1 is substantially lower. Differential recruitment to the HIV promoter and association with Human Polymerase-Associated Factor complex (PAFc) play key role in this functional distinction between AFF4 and AFF1. Moreover, while depletion of cyclin T1 expression has subtle effects on HIV gene transcription in the absence of Tat, knockout (KO) of AFF1, AFF4, or both proteins slightly repress this early step of viral transcription. Upon Tat expression, HIV transcription reaches optimal levels despite KO of AFF1 or AFF4 expression. However, double AFF1/AFF4 KO completely diminishes Tat trans-activation. Significantly, our results show that P-TEFb phosphorylates AFF4 and modulates SEC assembly, AFF1/4 dimerization and recruitment to the viral promoter. We conclude that SEC promotes both early steps of HIV transcription in the absence of Tat, as well as elongation of transcription, when Tat is expressed. Significantly, SEC functions are modulated by P-TEFb.
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· 2017 May · PMID 28340330
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Transcription factors TBP and TF(II)B assemble with RNA polymerase at the promoter DNA forming the initiation complex. Despite a high degree of conservation, the molecular binding mechanisms of archaeal and eukaryotic TB...Transcription factors TBP and TF(II)B assemble with RNA polymerase at the promoter DNA forming the initiation complex. Despite a high degree of conservation, the molecular binding mechanisms of archaeal and eukaryotic TBP and TF(II)B differ significantly. Based on recent biophysical data, we speculate how the mechanisms co-evolved with transcription regulation and TBP multiplicity.
Lerner E, Ingargiola A, Lee JJ
… +3 more, Borukhov S, Michalet X, Weiss S
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· 2017 Aug · PMID 28332923
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In many cases, initiation is rate limiting to transcription. This due in part to the multiple cycles of abortive transcription that delay promoter escape and the transition from initiation to elongation. Pausing of trans...In many cases, initiation is rate limiting to transcription. This due in part to the multiple cycles of abortive transcription that delay promoter escape and the transition from initiation to elongation. Pausing of transcription in initiation can further delay promoter escape. The previously hypothesized pausing in initiation was confirmed by two recent studies from Duchi et al. and from Lerner, Chung et al. In both studies, pausing is attributed to a lack of forward translocation of the nascent transcript during initiation. However, the two works report on different pausing mechanisms. Duchi et al. report on pausing that occurs during initiation predominantly on-pathway of transcript synthesis. Lerner, Chung et al. report on pausing during initiation as a result of RNAP backtracking, which is off-pathway to transcript synthesis. Here, we discuss these studies, together with additional experimental results from single-molecule FRET focusing on a specific distance within the transcription bubble. We show that the results of these studies are complementary to each other and are consistent with a model involving two types of pauses in initiation: a short-lived pause that occurs in the translocation of a 6-mer nascent transcript and a long-lived pause that occurs as a result of 1-2 nucleotide backtracking of a 7-mer transcript.
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· 2017 May · PMID 28301308
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Protein arginine methyltransferase (PRMT) is a family of nine proteins catalyzing the methylation of arginine residues. They were recently shown to be essential for proper regeneration of skeletal muscles. However, the m...Protein arginine methyltransferase (PRMT) is a family of nine proteins catalyzing the methylation of arginine residues. They were recently shown to be essential for proper regeneration of skeletal muscles. However, the mechanisms triggering the methylation event, as well as how the methylated substrates regulate muscle stem cell function and fate decision remain to be determined. This point-of-view will discuss the recent findings on the specific role of PRMT1, CARM1/PRMT4, PRMT5, and PRMT7 in muscle stem cell fate guidance, and shed light on the future challenges which could help defining the therapeutic potential of PRMT inhibitors against muscular disorders and aging.
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· 2017 May · PMID 28301306
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Pioneer transcription factors are defined by their ability to bind nucleosome-occupied regions. Here, we discuss the properties of nucleosomes bound by pioneers at enhancer regions. We describe how select pioneers bind n...Pioneer transcription factors are defined by their ability to bind nucleosome-occupied regions. Here, we discuss the properties of nucleosomes bound by pioneers at enhancer regions. We describe how select pioneers bind nucleosome-occupied or -depleted enhancer sites. Importantly, by revisiting and expanding existing data sets, we show differential H2A.Z and p300/CBP association at bound enhancers, highlighting two possible pioneering modes.
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· 2017 May · PMID 28301294
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Drosophila genetic studies demonstrate that cell and tissue growth regulation is a primary developmental function of P-element somatic inhibitor (Psi), the sole ortholog of FUBP family RNA/DNA-binding proteins. Psi achie...Drosophila genetic studies demonstrate that cell and tissue growth regulation is a primary developmental function of P-element somatic inhibitor (Psi), the sole ortholog of FUBP family RNA/DNA-binding proteins. Psi achieves growth control through interaction with Mediator, observations that should put to rest controversy surrounding Pol II transcriptional functions for these KH domain proteins.
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· 2017 May · PMID 28301293
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The ETS family of transcription factors is a functionally heterogeneous group of gene regulators that share a structurally conserved, eponymous DNA-binding domain. DNA target specificity derives from combinatorial intera...The ETS family of transcription factors is a functionally heterogeneous group of gene regulators that share a structurally conserved, eponymous DNA-binding domain. DNA target specificity derives from combinatorial interactions with other proteins as well as intrinsic heterogeneity among ETS domains. Emerging evidence suggests molecular hydration as a fundamental feature that defines the intrinsic heterogeneity in DNA target selection and susceptibility to epigenetic DNA modification. This perspective invokes novel hypotheses in the regulation of ETS proteins in physiologic osmotic stress, their pioneering potential in heterochromatin, and the effects of passive and pharmacologic DNA demethylation on ETS regulation.
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· 2017 May · PMID 28301289
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Mediator is a conserved and essential coactivator complex broadly required for RNA polymerase II (RNAPII) transcription. Recent genome-wide studies of Mediator binding in budding yeast have revealed new insights into the...Mediator is a conserved and essential coactivator complex broadly required for RNA polymerase II (RNAPII) transcription. Recent genome-wide studies of Mediator binding in budding yeast have revealed new insights into the functions of this critical complex and raised new questions about its role in the regulation of gene expression.
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· 2017 May · PMID 28301288
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This review is focused on recent progress in understanding how Escherichia coli RNAP polymerase translocates along the DNA template and the factors that affect this movement. We discuss the fundamental aspects of RNAP tr...This review is focused on recent progress in understanding how Escherichia coli RNAP polymerase translocates along the DNA template and the factors that affect this movement. We discuss the fundamental aspects of RNAP translocation, template signals that influence forward or backward movement, and host or phage factors that modulate translocation.
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· 2017 Mar · PMID 28151046
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Despite recent advances in structural analysis, it is still challenging to obtain a high-resolution structure for a complex of RNA polymerase, transcriptional factors, and DNA. However, using biochemical constraints, 3D...Despite recent advances in structural analysis, it is still challenging to obtain a high-resolution structure for a complex of RNA polymerase, transcriptional factors, and DNA. However, using biochemical constraints, 3D printed models of available structures, and computer modeling, one can build biologically relevant models of such supramolecular complexes.
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· 2017 Mar · PMID 28129043
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Transcriptional interference (TI) is increasingly recognized as a widespread mechanism of gene control, particularly given the pervasive nature of transcription, both sense and antisense, across all kingdoms of life. Her...Transcriptional interference (TI) is increasingly recognized as a widespread mechanism of gene control, particularly given the pervasive nature of transcription, both sense and antisense, across all kingdoms of life. Here, we discuss how transcription factor binding kinetics strongly influence the ability of a transcription factor to relieve or induce TI.
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· 2017 Mar · PMID 28102760
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We recently identified PHF13 as an H3K4me2/3 chromatin reader and transcriptional co-regulator. We found that PHF13 interacts with RNAPIIS5P and PRC2 stabilizing their association with active and bivalent promoters. Furt...We recently identified PHF13 as an H3K4me2/3 chromatin reader and transcriptional co-regulator. We found that PHF13 interacts with RNAPIIS5P and PRC2 stabilizing their association with active and bivalent promoters. Furthermore, mass spectrometry analysis identified ∼50 spliceosomal proteins in PHF13s interactome. Here, we will discuss the potential role of PHF13 in RNAPII pausing and co-transcriptional splicing.
The release of a paused Pol II depends on the recruitment of P-TEFb. Recent studies showed that both active P-TEFb and inactive P-TEFb (7SK snRNP) can be recruited to the promoter regions of global genes by different mec...The release of a paused Pol II depends on the recruitment of P-TEFb. Recent studies showed that both active P-TEFb and inactive P-TEFb (7SK snRNP) can be recruited to the promoter regions of global genes by different mechanisms. Here, we summarize the recent advances on these distinct recruitment mechanisms.