Histone acetylation targeting to transcribed chromatin through RNAPII
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA433380 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10197354_1.fastq.gz | Fastqsanger.gz | |||
| SRR10197354_2.fastq.gz | Fastqsanger.gz | |||
| SRR10197355_1.fastq.gz | Fastqsanger.gz | |||
| SRR10197355_2.fastq.gz | Fastqsanger.gz | |||
| SRR10197356_1.fastq.gz | Fastqsanger.gz |
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Project description:Histone acetylation is associated with active transcription and serves as a binding site for reader proteins that function in transcriptional initiation and elongation. Histone acetylation levels are regulated through the actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs) that antagonistically control the overall balance of this posttranslational modification. HDAC inhibitors (HDACi) are potent agents that disrupt this balance and are used clinically to treat a range of human diseases including cancer. Despite their clinical applications, little is known about their chromatin effects. By applying quantitative genomic and proteomic approaches, we demonstrate that HDACi robustly increase a low abundance histone acetylation state (H4 K5ac/K8ac/12ac/K16ac), which serves as a preferred binding substrate for a variety of human bromodomain-containing proteins, including BRD4. This H4 polyacetylation signature observed after HDACi treatment accumulates in the transcribed regions of genes and correlates with the targeting of BRD4 to genes with increased gene expression. Collectively, these results suggest that HDAC inhibition functions, at least in part, through expansion of a rare chromatin acetylation state, which then retargets lysine-acetyl reader proteins associated with changes in gene expression.
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Project description:N6-methyladenosine modification (m6A) fine-tunes RNA fate in a variety of ways, thus regulating multiple fundamental biological processes. m6A writers bind to chromatin and interact with RNA polymerase II (RNAPII) during transcription. To evaluate how the dynamics of the transcription process impact m6A deposition, we studied RNAPII elongation rates in mouse embryonic stem cells with altered chromatin configurations, due to reductions in linker histone H1 content. We found that genes transcribed at slow speed are preferentially methylated and display unique signatures at their promoter region, namely high levels of histone H1, together with marks of bivalent chromatin and low RNAPII pausing. They are also highly susceptible to m6A loss upon histone H1 reduction. These results indicate that RNAPII velocity links chromatin structure and the deposition of m6A, highlighting the intricate relationship between different regulatory layers on nascent mRNA molecules.
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Project description:RNA polymerase II (RNAPII) pausing release is a recently recognized checkpoint for transcriptional regulation. The biological roles of RNAPII pausing release and the mechanisms that by which extracellular signals control it are incompletely understood. Here we identify a novel mechanism by which VEGF stimulates RNAPII pausing-release through acetylation of ETS1, a master endothelial cell transcriptional regulator. In endothelial cells (ECs), ETS1 uniquely bound transcribed gene promoters and stimulated their expression by broadly increasing RNA polymerase II (RNAPII) pause release. VEGF enhanced ETS1 chromatin occupancy. Furthermore, VEGF increased ETS1 acetylation, enhancing its binding by BRD4 and thereby stimulating RNAPII pause release. This ETS1-mediated transduction of VEGF signaling to increase RNAPII pausing release was essential for EC angiogenic responses in vitro and in vivo. Together, our results define a new angiogenic pathway in which VEGF enhances ETS1-Brd4 interaction to broadly promote RNAPII pause release and drive angiogenesis.
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Project description:Histone acetylation governs broad gene expression programs in normal tissue and disease states. By applying a small chemical compound library targeting epigenetic regulators to a dual endogenous reporter system, we found that inhibiting histone deacetylase (HDAC) 1/2 initiates colorectal cancer (CRC) differentiation. Inhibiting the enzymatic pocket of HDAC1/2 induced differentiation and reduced proliferation across in vitro and in vivo models. On-target HDAC1/2 inhibition was validated using biochemical, chemical, and genetic approaches. A survey of histone posttranslational modifications from HDAC1/2 selective inhibition nominated acetylation of specific H3 and H4 lysine (K) residues as potential regulators of differentiation. Genome-wide profiles of these histone acetylation marks indicated that gains in histone 3 lysine 27 acetylation (H3K27ac) most strongly correlated to opening of chromatin and upregulation of genes associated with differentiation upon HDAC1/2 inhibition. Blocking acetylation of H3K27 by degrading its writer EP300 rescued the differentiation phenotype induced by HDAC1/2 inhibition in a patient-derived CRC model by single cell RNA-sequencing among other readouts. These results highlight the importance of specific chemically targetable histone modifications in governing cancer cell states and implicate precision targeting of H3K27ac as a potential therapeutic approach for CRC.
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Project description:Here we analysed the role of yeast Senataxin (Sen1) in coordinating replication with transcription and in protecting genome integrity. Senataxin is mutated in the two severe neurodegenerative diseases AOA2 and ALS4. We show that a fraction of Sen1/Senataxin DNA/RNA helicase associates with replication forks and protects the integrity of those fork encountering highly expressed RNAPII genes. sen1 mutants accumulate aberrant DNA structures and RNA-DNA hybrids while forks clash head-on with RNAPII transcription units and counteract recombinogenic events and accumulation of checkpoint signals. Nrd1, which acts togheter with Sen1 in trascription temination, is not recruited at replication forks. nrd1 mutants does not display replication defects, high genome instability and checkpoint activation observed in sen1 mutants The Sen1 function in replication can be therefore separable from its role in RNA processing. We propose a role for Sen1/Senataxin during chromosome replication in facilitating replisome progression across RNAPII transcribed genes thus preventing DNA-RNA hybrids accumulation when forks encounter nascent transcripts on the lagging strand template.
2012-11-09 | GSE39139 | GEO