scholarly journals Release of promoter–proximal paused Pol II in response to histone deacetylase inhibition

2020 ◽  
Vol 48 (9) ◽  
pp. 4877-4890 ◽  
Author(s):  
Roshan Vaid ◽  
Jiayu Wen ◽  
Mattias Mannervik
Keyword(s):  
Histone Acetylation ◽  
Rna Polymerase Ii ◽  
Histone Deacetylase ◽  
Transcriptional Response ◽  
Feedback Regulation ◽  
Hdac Inhibition ◽  
Pol Ii ◽  
Histone Deacetylase Inhibition ◽  
Enhanced Expression ◽  
Long Time

Abstract A correlation between histone acetylation and transcription has been noted for a long time, but little is known about what step(s) in the transcription cycle is influenced by acetylation. We have examined the immediate transcriptional response to histone deacetylase (HDAC) inhibition, and find that release of promoter–proximal paused RNA polymerase II (Pol II) into elongation is stimulated, whereas initiation is not. Although histone acetylation is elevated globally by HDAC inhibition, less than 100 genes respond within 10 min. These genes are highly paused, are strongly associated with the chromatin regulators NURF and Trithorax, display a greater increase in acetylation of the first nucleosomes than other genes, and become transcriptionally activated by HDAC inhibition. Among these rapidly up-regulated genes are HDAC1 (Rpd3) and subunits of HDAC-containing co-repressor complexes, demonstrating feedback regulation upon HDAC inhibition. Our results suggest that histone acetylation stimulates transcription of paused genes by release of Pol II into elongation, and that increased acetylation is not a consequence of their enhanced expression. We propose that HDACs are major regulators of Pol II pausing and that this partly explains the presence of HDACs at active genes.

scholarly journals Genome-Wide STAT3 Binding Analysis after Histone Deacetylase Inhibition Reveals Novel Target Genes in Dendritic Cells

2016 ◽  
Vol 9 (2) ◽  
pp. 126-144 ◽  
Author(s):  
Yaping Sun ◽  
Matthew Iyer ◽  
Richard McEachin ◽  
Meng Zhao ◽  
Yi-Mi Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dendritic Cells ◽  
Histone Deacetylase ◽  
Antigen Processing ◽  
Target Genes ◽  
Hdac Inhibition ◽  
Histone Deacetylase Inhibition ◽  
Immune Effector ◽  
Chip Sequencing ◽  
Genome Wide

STAT3 is a master transcriptional regulator that plays an important role in the induction of both immune activation and immune tolerance in dendritic cells (DCs). The transcriptional targets of STAT3 in promoting DC activation are becoming increasingly understood; however, the mechanisms underpinning its role in causing DC suppression remain largely unknown. To determine the functional gene targets of STAT3, we compared the genome-wide binding of STAT3 using ChIP sequencing coupled with gene expression microarrays to determine STAT3-dependent gene regulation in DCs after histone deacetylase (HDAC) inhibition. HDAC inhibition boosted the ability of STAT3 to bind to distinct DNA targets and regulate gene expression. Among the top 500 STAT3 binding sites, the frequency of canonical motifs was significantly higher than that of noncanonical motifs. Functional analysis revealed that after treatment with an HDAC inhibitor, the upregulated STAT3 target genes were those that were primarily the negative regulators of proinflammatory cytokines and those in the IL-10 signaling pathway. The downregulated STAT3-dependent targets were those involved in immune effector processes and antigen processing/presentation. The expression and functional relevance of these genes were validated. Specifically, functional studies confirmed that the upregulation of IL-10Ra by STAT3 contributed to the suppressive function of DCs following HDAC inhibition.

scholarly journals Stress-Induced Transcriptional Memory Accelerates Promoter-Proximal Pause-Release and Decelerates Termination over Mitotic Divisions

2019 ◽  
Author(s):  
Anniina Vihervaara ◽  
Dig Bijay Mahat ◽  
Samu V. Himanen ◽  
Malin A.H. Blom ◽  
John T. Lis ◽  
...  
Keyword(s):  
Heat Shock ◽  
Rna Polymerase Ii ◽  
Transcriptional Response ◽  
Regulatory Elements ◽  
List Type ◽  
Pol Ii ◽  
Daughter Cells ◽  
Heat Shocks ◽  
Transcriptional Memory ◽  
Pol Ii Pausing

SummaryHeat shock triggers an instant reprogramming of gene and enhancer transcription, but whether cells encode a memory to stress, at the level of nascent transcription, has remained unknown. Here, we measured transcriptional response to acute heat stress in unconditioned cells and in daughters of cells that had been exposed to a single or multiple heat shocks. Tracking RNA Polymerase II (Pol II) genome-wide at nucleotide-resolution revealed that cells precisely remember their transcriptional identity throughout stress, restoring Pol II distribution at gene bodies and enhancers upon recovery. However, single heat shock primed faster gene-induction in the daughter cells by increasing promoter-proximal Pol II pausing, and accelerating the pause-release. In repeatedly stressed cells, both basal and inducible transcription was refined, and pre-mRNA processing decelerated, which retained transcripts on chromatin and reduced recycling of the transcription machinery. These results mechanistically uncovered how the steps of pause-release and termination maintain transcriptional memory over mitosis.Highlights-Cell type-specific transcription precisely recovers after heat-induced reprogramming-Single heat shock primes genes for accelerated induction over mitotic divisionsviaincreased promoter-proximal Pol II pausing and faster pause-release-Multiple heat shocks refine basal and inducible transcription over mitotic divisions to support survival of the daughter cells-Decelerated termination at active genes reduces recycling of Pol II to heat-activated promoters and enhancers-HSF1 increases the rate of promoter-proximal pause-releaseviadistal and proximal regulatory elements

scholarly journals β-Globin Intergenic Transcription and Histone Acetylation Dependent on an Enhancer

2007 ◽  
Vol 27 (8) ◽  
pp. 2980-2986 ◽  
Author(s):  
AeRi Kim ◽  
Hui Zhao ◽  
Ina Ifrim ◽  
Ann Dean
Keyword(s):  
Histone Acetylation ◽  
Rna Polymerase Ii ◽  
Target Gene ◽  
Globin Gene ◽  
Tata Box ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Transcription Complexes ◽  
And Function ◽  
H3 Acetylation

ABSTRACT Histone acetyltransferases are associated with the elongating RNA polymerase II (Pol II) complex, supporting the idea that histone acetylation and transcription are intertwined mechanistically in gene coding sequences. Here, we studied the establishment and function of histone acetylation and transcription in noncoding sequences by using a model locus linking the β-globin HS2 enhancer and the embryonic ε-globin gene in chromatin. An intact HS2 enhancer that recruits RNA Pol II is required for intergenic transcription and histone H3 acetylation and K4 methylation between the enhancer and target gene. RNA Pol II recruitment to the target gene TATA box is not required for the intergenic transcription or intergenic histone modifications, strongly implying that they are properties conferred by the enhancer. However, Pol II recruitment at HS2, intergenic transcription, and intergenic histone modification are not sufficient for transcription or modification of the target gene: these changes require initiation at the TATA box of the gene. The results suggest that intergenic and genic transcription complexes are independent and possibly differ from one another.

scholarly journals Maize RAMOSA3 accumulates in nuclear condensates enriched in RNA POLYMERASE II isoforms during the establishment of axillary meristem determinacy.

2021 ◽  
Author(s):  
Edgar Demesa-Arevalo ◽  
Maria Jazmin Abraham-Juarez ◽  
Xiaosa Xu ◽  
Madelaine Bartlett ◽  
David Jackson
Keyword(s):  
Rna Polymerase Ii ◽  
Chromatin Remodeling ◽  
Transcriptional Response ◽  
Mrna Processing ◽  
Nuclear Speckles ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Imaging Processing ◽  
Whole Mount ◽  
Double Immunolabeling

Maize meristem determinacy is regulated by Trehalose-6-Phosphate Phosphatase (TPP) metabolic enzymes RAMOSA3 and TPP4. However, this function is independent of their enzymatic activity, suggesting they have an unpredicted, or moonlighting function. Using whole-mount double immunolabeling and imaging processing, we investigated the co-localization of RA3 nuclear speckles with markers for transcription, chromatin state and splicing. We find evidence for RA3 co-localization with RNA POL II, a transcription marker, and not with markers for promoter chromatin remodeling or mRNA processing, suggesting a function of nuclear RA3 in mediating a transcriptional response during meristem determinacy.

scholarly journals P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress

2018 ◽  
Author(s):  
Andrii Bugai ◽  
Alexandre J.C. Quaresma ◽  
Caroline C. Friedel ◽  
Tina Lenasi ◽  
Christopher R. Sibley ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase Ii ◽  
Cell Fate ◽  
Rna Binding ◽  
Transcriptional Response ◽  
Genotoxic Stress ◽  
Binding Motif ◽  
Pol Ii ◽  
Small Nuclear Ribonucleoprotein ◽  
Stress Dependent

SUMMARYCellular DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill-defined. Given the centrality of RNA polymerase II (Pol II) promoter-proximal pause release in transcriptional control, we evaluated its importance in DDR. Here we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates Pol II elongation and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb). This is mediated by genotoxic stress-enhanced binding of RBM7 to 7SK snRNA (7SK), the scaffold of the 7SK small nuclear ribonucleoprotein (7SK snRNP) which inhibits P-TEFb. In turn, P-TEFb relocates from 7SK snRNP to chromatin to induce transcription of short units including key DDR genes and multiple classes of non-coding RNAs. Critically, interfering with RBM7 or P-TEFb provokes cellular hypersensitivity to DNA damage-inducing agents through activation of apoptotic program. By alleviating the inhibition of P-TEFb, RBM7 thus facilitates Pol II elongation to enable a pro-survival transcriptional response that is crucial for cell fate upon genotoxic insult. Our work uncovers a new paradigm in stress-dependent control of Pol II pause release, and offers the promise for designing novel anti-cancer interventions using RBM7 and P-TEFb antagonists in combination with DNA-damaging chemotherapeutics.

scholarly journals Hyperosmotic stress induces downstream-of-gene transcription and alters the RNA Polymerase II interactome despite widespread transcriptional repression

2020 ◽  
Author(s):  
Nicolle A. Rosa-Mercado ◽  
Joshua T. Zimmer ◽  
Maria Apostolidi ◽  
Jesse Rinehart ◽  
Matthew D. Simon ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Transcriptional Repression ◽  
Transcriptional Response ◽  
Hyperosmotic Stress ◽  
Transcriptional Level ◽  
List Type ◽  
Upstream Gene ◽  
Pol Ii ◽  
Transcription Profiles

SummaryStress-induced readthrough transcription results in the synthesis of thousands of downstream-of-gene (DoG) containing transcripts. The mechanisms underlying DoG formation during cellular stress remain unknown. Nascent transcription profiles during DoG induction in human cell lines using TT-TimeLapse-seq revealed that hyperosmotic stress induces widespread transcriptional repression. Yet, DoGs are produced regardless of the transcriptional level of their upstream genes. ChIP-seq confirmed that the stress-induced redistribution of RNA Polymerase (Pol) II correlates with the transcriptional output of genes. Stress-induced alterations in the Pol II interactome are observed by mass spectrometry. While subunits of the cleavage and polyadenylation machinery remained Pol II-associated, Integrator complex subunits dissociated from Pol II under stress conditions. Depleting the catalytic subunit of the Integrator complex, Int11, using siRNAs induces hundreds of readthrough transcripts, whose parental genes partially overlap those of stress-induced DoGs. Our results provide insights into the mechanisms underlying DoG production and how Integrator activity influences DoG transcription.In briefRosa-Mercado et al. report that hyperosmotic stress causes widespread transcriptional repression in human cells, yet DoGs arise regardless of the transcriptional response of their upstream genes. They find that the interaction between Pol II and Integrator is disrupted by hypertonicity and that knocking down the Integrator nuclease leads to DoG production.HighlightsHyperosmotic stress triggers transcriptional repression of many genes.DoG RNAs arise independent of the transcriptional level of their upstream gene.The interaction between Pol II and Integrator subunits decreases after salt stress.Depletion of the Int11 nuclease subunit induces the production of hundreds of DoGs.

scholarly journals Histone Deacetylase 7 and FoxA1 in Estrogen-Mediated Repression of RPRM

2009 ◽  
Vol 30 (2) ◽  
pp. 399-412 ◽  
Author(s):  
Simeen Malik ◽  
Shiming Jiang ◽  
Jason P. Garee ◽  
Eric Verdin ◽  
Adrian V. Lee ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Histone Deacetylase ◽  
Transcriptional Activity ◽  
Estrogen Receptor Α ◽  
Proximal Promoter ◽  
Pol Ii ◽  
Cell Cycle Inhibitor ◽  
Pioneer Factor ◽  
A Cell ◽  
Estrogen Induction

ABSTRACT Activation of estrogen receptor α (ERα) results in both induction and repression of gene transcription; while mechanistic details of estrogen induction are well described, details of repression remain largely unknown. We characterized several ERα-repressed targets and examined in detail the mechanism for estrogen repression of Reprimo (RPRM), a cell cycle inhibitor. Estrogen repression of RPRM is rapid and robust and requires a tripartite interaction between ERα, histone deacetylase 7 (HDAC7), and FoxA1. HDAC7 is the critical HDAC needed for repression of RPRM; it can bind to ERα and represses ERα's transcriptional activity—this repression does not require HDAC7's deacetylase activity. We further show that the chromatin pioneer factor FoxA1, well known for its role in estrogen induction of genes, is recruited to the RPRM promoter, is necessary for repression of RPRM, and interacts with HDAC7. Like other FoxA1 recruitment sites, the RPRM promoter is characterized by H3K4me1/me2. Estrogen treatment causes decreases in H3K4me1/me2 and release of RNA polymerase II (Pol II) from the RPRM proximal promoter. Overall, these data implicate a novel role for HDAC7 and FoxA1 in estrogen repression of RPRM, a mechanism which could potentially be generalized to many more estrogen-repressed genes and hence be important in both normal physiology and pathological processes.

scholarly journals Transcription-dependent targeting of Hda1C to hyperactive genes mediates H4-specific deacetylation in yeast

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
So Dam Ha ◽  
Seokjin Ham ◽  
Min Young Kim ◽  
Ji Hyun Kim ◽  
Insoon Jang ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Histone Deacetylase ◽  
Transcriptional Response ◽  
Gene Induction ◽  
Fine Tuning ◽  
Histone H4 ◽  
Histone H4 Acetylation ◽  
Inactive Genes ◽  
Kinetics Of

Abstract In yeast, Hda1 histone deacetylase complex (Hda1C) preferentially deacetylates histones H3 and H2B, and functionally interacts with Tup1 to repress transcription. However, previous studies identified global increases in histone H4 acetylation in cells lacking Hda1, a component of Hda1C. Here, we find that Hda1C binds to hyperactive genes, likely via the interaction between the Arb2 domain of Hda1 and RNA polymerase II. Additionally, we report that Hda1C specifically deacetylates H4, but not H3, at hyperactive genes to partially inhibit elongation. This role is contrast to that of the Set2–Rpd3S pathway deacetylating histones at infrequently transcribed genes. We also find that Hda1C deacetylates H3 at inactive genes to delay the kinetics of gene induction. Therefore, in addition to fine-tuning of transcriptional response via H3-specific deacetylation, Hda1C may modulate elongation by specifically deacetylating H4 at highly transcribed regions.

scholarly journals Histone Deacetylase Inhibitor Improves the Dysfunction of Hippocampal Gamma Oscillations and Fast Spiking Interneurons in Alzheimer’s Disease Model Mice

2021 ◽  
Vol 14 ◽  
Author(s):  
Keiko Takasu ◽  
Kazuki Niidome ◽  
Minoru Hasegawa ◽  
Koichi Ogawa
Keyword(s):  
Alzheimer’S Disease ◽  
Cognitive Impairment ◽  
Cognitive Function ◽  
Histone Acetylation ◽  
Histone Deacetylase ◽  
Gamma Oscillations ◽  
Gamma Oscillation ◽  
Hdac Inhibition ◽  
Activated State ◽  
Fast Spiking

The hippocampal gamma oscillation is important for cognitive function, and its deficit is related to cognitive impairment in Alzheimer’s disease (AD). Recently, it has been recognized that post-translational modification via histone acetylation is a fundamental molecular mechanism for regulating synaptic plasticity and cognitive function. However, little is known regarding the regulation of hippocampal gamma oscillation by histone acetylation. We investigated whether histone acetylation regulated kainate-induced gamma oscillations and their important regulator, fast-spiking interneurons, using acute hippocampal slices of AD model mice (PSAPP transgenic mice). We found a decrease in kainate-induced gamma oscillations in slices from PSAPP mice, accompanied with the increased activity of fast spiking interneurons in basal state and the decreased activity in activated state. The histone deacetylase (HDAC) inhibitor (SAHA, named vorinostat) restored deficits of gamma oscillation in PSAPP mice, accompanied with rescue of activity of fast spiking interneurons in basal and activated state. The effect of SAHA was different from that of the clinical AD drug donepezil, which rescued only function of fast spiking interneurons in basal state. Besides, activator of nuclear receptor family 4a (NR4a) receptor (cytosporone B), as one of the epigenetic modification related to HDAC inhibition, rescued the deficits in gamma oscillations in PSAPP mice. These results suggested a novel mechanism in which HDAC inhibition improved impairment of gamma oscillations in PSAPP mice by restoring the activity of fast spiking interneurons both in basal and activated state. The reversal of gamma oscillation deficits by HDAC inhibition and/or NR4a activation appears to be a potential therapeutic target for treating cognitive impairment in AD patients.

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