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Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE162896 | GEO | 2021/12/31

REPOSITORIES: GEO

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Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [RNA-seq]

Project description:Histone proteolysis is a poorly understood phenomena by which the N-terminal tail of histones are irreversible cleaved by intracellular proteases. During development histone PTMs are known orchestrate gene expression and ultimately cell fate decision, therefore it will be key to decipher underlying mechanisms that lead to proteolysis during cellular differentiation. Previous reports have found that histone H2A is cleaved at the C-terminus, and here we found that the N-terminal is also proteolytically clipped and removed by the lysosomal protease Cathepsin L. Using quantitative mass spectrometry (MS), we identified L23 to be the primary site for this protease, with this clipped H2A (cH2A) form representing ~1% of the total H2A reaching a maximum after 4 days of differentiation. Using Chip-seq, we found reduced proteolysis, lead to increase acetylated H2A at promoter regions in differentiated ES cells. We also report novel readers of acetylated H2A during in pluripotency as we identified members of the pBAF complex to recognize different forms of H2A acetylation. Moreover, our data showed that this recognition is abolished upon proteolysis. All in, our data suggest that proteolysis serve as a quick mechanism to silence genes involve in pluripotency and destabilize the nucleosome core particle as indicated by protein degradation studies.

2021-12-31 | GSE162877 | GEO

Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [H2AK9ac ChIP-seq]

2021-12-31 | GSE162874 | GEO

Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [ARID2 and PBRM1 ChIP-seq]

2022-03-22 | GSE196205 | GEO

Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation

Project description:Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation

| PRJNA683655 | ENA

Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [RNA-seq]

Project description:Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [RNA-seq]

| PRJNA683626 | ENA

Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [H2AK9ac ChIP-seq]

Project description:Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [H2AK9ac ChIP-seq]

| PRJNA683657 | ENA

Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [ARID2 and PBRM1 ChIP-seq]

Project description:Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [ARID2 and PBRM1 ChIP-seq]

| PRJNA803895 | ENA

Monoubiquitinated histone H2A destabilizes photolesion-containing nucleosomes with concomitant release of UV-damaged DNA-binding protein E3 ligase.

Project description:How the nucleotide excision repair (NER) machinery gains access to damaged chromatinized DNA templates and how the chromatin structure is modified to promote efficient repair of the non-transcribed genome remain poorly understood. The UV-damaged DNA-binding protein complex (UV-DDB, consisting of DDB1 and DDB2, the latter of which is mutated in xeroderma pigmentosum group E patients, is a substrate-recruiting module of the cullin 4B-based E3 ligase complex, DDB1-CUL4B(DDB2). We previously reported that the deficiency of UV-DDB E3 ligases in ubiquitinating histone H2A at UV-damaged DNA sites in the xeroderma pigmentosum group E cells contributes to the faulty NER in these skin cancer-prone patients. Here, we reveal the mechanism by which monoubiquitination of specific H2A lysine residues alters nucleosomal dynamics and subsequently initiates NER. We show that DDB1-CUL4B(DDB2) E3 ligase specifically binds to mononucleosomes assembled with human recombinant histone octamers and nucleosome-positioning DNA containing cyclobutane pyrimidine dimers or 6-4 photoproducts photolesions. We demonstrate functionally that ubiquitination of H2A Lys-119/Lys-120 is necessary for destabilization of nucleosomes and concomitant release of DDB1-CUL4B(DDB2) from photolesion-containing DNA. Nucleosomes in which these lysines are replaced with arginines are resistant to such structural changes, and arginine mutants prevent the eviction of H2A and dissociation of polyubiquitinated DDB2 from UV-damaged nucleosomes. The partial eviction of H3 from the nucleosomes is dependent on ubiquitinated H2A Lys-119/Lys-120. Our results provide mechanistic insight into how post-translational modification of H2A at the site of a photolesion initiates the repair process and directly affects the stability of the human genome.

| S-EPMC3320950 | biostudies-literature

Histone H2A variants in nucleosomes and chromatin: more or less stable?

Project description:In eukaryotes, DNA is organized together with histones and non-histone proteins into a highly complex nucleoprotein structure called chromatin, with the nucleosome as its monomeric subunit. Various interconnected mechanisms regulate DNA accessibility, including replacement of canonical histones with specialized histone variants. Histone variant incorporation can lead to profound chromatin structure alterations thereby influencing a multitude of biological processes ranging from transcriptional regulation to genome stability. Among core histones, the H2A family exhibits highest sequence divergence, resulting in the largest number of variants known. Strikingly, H2A variants differ mostly in their C-terminus, including the docking domain, strategically placed at the DNA entry/exit site and implicated in interactions with the (H3-H4)(2)-tetramer within the nucleosome and in the L1 loop, the interaction interface of H2A-H2B dimers. Moreover, the acidic patch, important for internucleosomal contacts and higher-order chromatin structure, is altered between different H2A variants. Consequently, H2A variant incorporation has the potential to strongly regulate DNA organization on several levels resulting in meaningful biological output. Here, we review experimental evidence pinpointing towards outstanding roles of these highly variable regions of H2A family members, docking domain, L1 loop and acidic patch, and close by discussing their influence on nucleosome and higher-order chromatin structure and stability.

| S-EPMC3510494 | biostudies-literature

Histone H2A variants confer specific properties to nucleosomes and impact on chromatin accessibility.

Project description:In eukaryotes, variants of core histone H2A are selectively incorporated in distinct functional domains of chromatin and are distinguished by conserved sequences of their C-terminal tail, the L1 loop and the docking domain, suggesting that each variant confers specific properties to the nucleosome. Chromatin of flowering plants contains four types of H2A variants, which biochemical properties have not been characterized. We report that in contrast with animals, in Arabidopsis thaliana H2A variants define only four major types of homotypic nucleosomes containing exclusively H2A, H2A.Z, H2A.X or H2A.W. In vitro assays show that the L1 loop and the docking domain confer distinct stability of the nucleosome. In vivo and in vitro assays suggest that the L1 loop and the docking domain cooperate with the C-terminal tail to regulate chromatin accessibility. Based on these findings we conclude that the type of H2A variant in the nucleosome impacts on its interaction with DNA and propose that H2A variants regulate the dynamics of chromatin accessibility. In plants, the predominance of homotypic nucleosomes with specific physical properties and their specific localization to distinct domains suggest that H2A variants play a dominant role in chromatin dynamics and function.

| S-EPMC6125630 | biostudies-literature

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