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H3K4me2/3 modulate the stability of RNA polymerase II pausing (RNA-Seq)

ABSTRACT: Modifications of histones are intricately linked with the regulation of gene expression, with demonstrated roles in various physiological processes and disease pathogenesis. Methylation of histone H3 lysine 4 (H3K4), implemented by the COMPASS family, is enriched at promoters and associated cis-regulatory elements, with H3K4 trimethylation (H3K4me3) considered a hallmark of active gene promoters. However, the relative roles of deposition and removal of H3K4 methylation, as well as the extent to which these events contribute to transcriptional regulation have so far remained unclear. Here, through rapid depletion of either of two shared subunits of COMPASS family members, we reveal a dynamic turnover of H3K4me2 and H3K4me3 mediated by the KDM5 family of histone demethylases. Loss of H3K4me2 and H3K4me3 following COMPASS disruption does not impair the recruitment of TFIID and initiating RNA polymerase II (Pol II). Instead, their loss leads to reductions in the paused form of Pol II on chromatin while inducing the relative enrichment of the Integrator-PP2A (INTAC) termination complex, leading to reduced levels of elongating polymerases, thus revealing how H3K4me2 and H3K4me3 dynamics can regulate Pol II pausing to sustain or attenuate transcription.

ORGANISM(S): Mus musculus

PROVIDER: GSE222847 | GEO | 2023/03/18

REPOSITORIES: GEO

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H3K4me2/3 modulate the stability of RNA polymerase II pausing (ChIP-Seq)

Project description:Modifications of histones are intricately linked with the regulation of gene expression, with demonstrated roles in various physiological processes and disease pathogenesis. Methylation of histone H3 lysine 4 (H3K4), implemented by the COMPASS family, is enriched at promoters and associated cis-regulatory elements, with H3K4 trimethylation (H3K4me3) considered a hallmark of active gene promoters. However, the relative roles of deposition and removal of H3K4 methylation, as well as the extent to which these events contribute to transcriptional regulation have so far remained unclear. Here, through rapid depletion of either of two shared subunits of COMPASS family members, we reveal a dynamic turnover of H3K4me2 and H3K4me3 mediated by the KDM5 family of histone demethylases. Loss of H3K4me2 and H3K4me3 following COMPASS disruption does not impair the recruitment of TFIID and initiating RNA polymerase II (Pol II). Instead, their loss leads to reductions in the paused form of Pol II on chromatin while inducing the relative enrichment of the Integrator-PP2A (INTAC) termination complex, leading to reduced levels of elongating polymerases, thus revealing how H3K4me2 and H3K4me3 dynamics can regulate Pol II pausing to sustain or attenuate transcription.

2023-03-18 | GSE222845 | GEO

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Histone H3 lysine 4 trimethylation regulates RNA polymerase II promoter-proximal pause-release

Project description:Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and proposed to regulate transcription initiation. However, redundant functions of the H3K4 SET1/COMPASS methyltransferase complexes complicate elucidation of the specific role of H3K4me3 in transcriptional regulation. Here, we show that acute ablation of shared subunits of the SET1/COMPASS complexes leads to complete loss of all H3K4 methylation. H3K4me3 turnover occurs more rapidly than H3K4me1 and H3K4me2 and is dependent on KDM5 demethylases. Surprisingly, acute loss of H3K4me3 does not have detectable effects on transcriptional initiation but leads to a widespread decrease in transcriptional output, an increase in RNA polymerase II (RNAPII) pausing and slower elongation. Our study demonstrates a distinct role for H3K4me3 in transcriptional pause-release and elongation rather than transcriptional initiation.

2023-03-14 | PXD028858 | Pride

H3K4me3 regulates RNA polymerase II promoter-proximal pause-release

Project description:Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and proposed to regulate transcription initiation. However, redundant functions of the H3K4 SET1/COMPASS methyltransferase complexes complicate elucidation of the specific role of H3K4me3 in transcriptional regulation. Here, by using mouse embryonic stem cells (mESCs) as a model system, we show that acute ablation of shared subunits of the SET1/COMPASS complexes leads to complete loss of all H3K4 methylation. H3K4me3 turnover occurs more rapidly than H3K4me1 and H3K4me2 and is dependent on KDM5 demethylases. Surprisingly, acute loss of H3K4me3 does not have detectable effects on transcriptional initiation but leads to a widespread decrease in transcriptional output, an increase in RNA polymerase II (RNAPII) pausing and slower elongation. Notably, we show that H3K4me3 is required for the recruitment of the Integrator Complex Subunit 11 (INTS11), which is essential for the eviction of paused RNAPII and transcriptional elongation. Thus, our study demonstrates a distinct role for H3K4me3 in transcriptional pause-release and elongation rather than transcriptional initiation.

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Determinants of H3K4me pattern establishment

Project description:A hallmark of genes transcribed by RNA polymerase II (RNApII) is a "gradient" of histone H3 lysine 4 (H3K4) methylation. Various factors differentially bind to H3K4me3 near promoters, H3K4me2 just downstream, and H3K4me1 further downstream to modulate gene expression. Set1/COMPASS, the single S. cerevisiae H3K4 methyltransferase, binds transcribing RNApII, but COMPASS may also be allosterically regulated by specific subunits and histone H2B ubiquitylation. To ask whether differential H3K4 methylation is determined by regulated activity at specific gene locations or by the amount of time COMPASS spends near the nucleosome, ChIP-Seq analyses was performed in cells with altered transcription elongation rates or with Set1 fused to RNApII. Our results support a simple model where higher H3K4 methylations result from both increased duration and frequency of COMPASS proximity to the nucleosome.

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The MLL3/MLL4 branch of the COMPASS family regulates H3K4 monomethylation at enhancers

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2013-08-11 | E-GEOD-48172 | biostudies-arrayexpress

The Set1 complex is dimeric and acts with Proof Only Jhd2 demethylation to convey symmetrical H3K4 trimethylation [Spike-in-ChIP-seq]

Project description:Epigenetic that deposit and/or propagate symmetry or asymmetry are not understood. Here we report that yeast Set1C/ COMPASS (complex of proteins associated with Set1) is dimeric and, consequently, symmetrically trimethylates histone 3 Lys4 (H3K4me3) on promoter nucleosomes. Mutation of the dimer interface to make Set1C monomeric abolished H3K4me3 on most promoters. The most active promoters, particularly those involved in the oxidative phase of the yeast metabolic cycle, displayed H3K4me2, which is normally excluded from active promoters, and a subset of these also displayed H3K4me3. In wild-type yeast, deletion of the sole H3K4 demethylase, Jhd2, has no effect. However, in monomeric Set1C yeast, Jhd2 deletion increased H3K4me3 levels on the H3K4me2 promoters. Notably, the association of Set1C with the elongating polymerase was not perturbed by monomerization. These results imply that symmetrical H3K4 methylation is an embedded consequence of Set1C dimerism and that Jhd2 demethylates asymmetric H3K4me3. Consequently, rather than methylation and demethylation acting in opposition as logic would suggest, a dimeric methyltransferase and monomeric demethylase cooperate to eliminate asymmetry and focus symmetrical H3K4me3 onto selected nucleosomes. This presents a new paradigm for the establishment of epigenetic detail.

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