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Acetylation at the lateral surface of the nucleosome at lysine 64 of H3 regulates chromatin dynamics and defines transcriptionally active chromatin

ABSTRACT: Post-translational modifications of proteins have emerged as a major mechanism for regulating gene expression. Yet our understanding of how histone modifications directly affect chromatin function remains limited. Here, we investigate acetylation of histone H3 at lysine 64 (H3K64ac), a previously uncharacterized acetylation site on the lateral surface of the histone octamer. We show that H3K64ac regulates nucleosome dynamics by (i) destabilizing nucleosomes, and (ii) regulating chromatin remodelling. Both of these functions have the potential to regulate gene expression. In line with this, we show that the p300 co-activator acetylates H3K64 both in vitro and in vivo. H3K64ac is enriched at the transcriptional start sites (TSS) of active genes and defines transcriptionally active chromatin in ES cells. Moreover, we find that H3K64ac is dynamic during developmental reprogramming, and during mammalian spermatogenesis where H3K64 hyperacetylation precedes histone replacement. Consistent with a function in transcriptional activation, H3K64ac opposes its repressive counterpart H3K64me3. Our findings reveal an important role for a histone modification within the nucleosome core as a regulator of chromatin function in vivo and they demonstrate that lateral surface modifications can define functionally opposing chromatin states.

ORGANISM(S): Mus musculus

PROVIDER: GSE35355 | GEO | 2014/03/18

SECONDARY ACCESSION(S): PRJNA152737

REPOSITORIES: GEO

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Acetylation at the lateral surface of the nucleosome at lysine 64 of H3 regulates chromatin dynamics and defines transcriptionally active chromatin

Project description:Post-translational modifications of proteins have emerged as a major mechanism for regulating gene expression. Yet our understanding of how histone modifications directly affect chromatin function remains limited. Here, we investigate acetylation of histone H3 at lysine 64 (H3K64ac), a previously uncharacterized acetylation site on the lateral surface of the histone octamer. We show that H3K64ac regulates nucleosome dynamics by (i) destabilizing nucleosomes, and (ii) regulating chromatin remodelling. Both of these functions have the potential to regulate gene expression. In line with this, we show that the p300 co-activator acetylates H3K64 both in vitro and in vivo. H3K64ac is enriched at the transcriptional start sites (TSS) of active genes and defines transcriptionally active chromatin in ES cells. Moreover, we find that H3K64ac is dynamic during developmental reprogramming, and during mammalian spermatogenesis where H3K64 hyperacetylation precedes histone replacement. Consistent with a function in transcriptional activation, H3K64ac opposes its repressive counterpart H3K64me3. Our findings reveal an important role for a histone modification within the nucleosome core as a regulator of chromatin function in vivo and they demonstrate that lateral surface modifications can define functionally opposing chromatin states. In this study, 2 biological replicate samples for H3K64ac ChIP and one sample of H3K9ac ChIP in mouse emryonic stem cells were analyzed using custom designed Nimblegen HD2.1oligonucleotide tiling arrays.

2014-03-18 | E-GEOD-35355 | biostudies-arrayexpress

Mnase-seq for six histone mutants and two wild-types in S. cerevisiae

Project description:Nucleosome structure directly influences gene transcription. However, the function of each histone residue remains largely unknown. Here we profiled gene expression changes upon the mutation of individual residues of histone H3 and H4. Histone residues grouped by expression change similarity displayed overall structural relevance. This regulatory functional map of the core histones led to novel findings. First, the residues specific to each histone family tend to be more influential than those commonly found among different histones. Second, unlike histone acetylations, H3K4 trimethylation does not appear to be prerequisite for gene activation. Third, H3Q5 has been newly identified for its putative interactions with many chromatin regulators for transcription control. Lastly, the nucleosome lateral surface seems to play a key role through interactions with the surrounding DNA. Remarkably, we discovered a novel role for H3K56 in chromatin dynamics. The deletion of this residue, but not the alteration of acetylation states, caused a genome-wide decrease in nucleosome mobility and stabilized nucleosome positioning near transcription start and end sites. Occupying the DNA entry/exit site, H3K56 is thought to modulate nucleosome sliding along DNA. Taken together, genomics approaches such as microarray and deep sequencing prove valuable for mapping the function of histone residues. Performing Mnase-seq for six histone mutants and two wild-types in Saccharomyces cerevisiae

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The BAF complex enhances transcription through interaction with H3K56ac in the histone globular domain

Project description:Histone post-translational modifications play pivotal roles in eukaryotic gene expression. To date, most studies have focused on modifications in unstructured histone N-terminal tail domains and their binding proteins. However, transcriptional regulation by chromatin-effector proteins that directly recognize modifications in histone globular domains has yet to be clearly demonstrated, despite the richness of their multiple modifications. Here, we show that the ATP-dependent chromatin-remodeling BAF complex stimulates p53-dependent transcription through direct interaction with H3K56ac located on the lateral surface of the histone globular domain. Mechanistically, the BAF complex recognizes nucleosomal H3K56ac via the DPF domain in the DPF2 subunit and exhibits enhanced nucleosome-remodeling activity in the presence of H3K56ac. We further demonstrate that a defect in H3K56ac–BAF complex interaction leads to impaired p53-dependent gene expression and DNA damage responses. Our study provides direct evidence that histone globular domain modifications participate in the regulation of gene expression.

2024-09-30 | PXD051883 | JPOST Repository

Crosslinking mass spectrometry of the p300 catalytic core complexed with the nucleosome

Project description:p300 is a histone acetyltransferase that associates with crucial biological processes. p300 acetylates all four histones in the nucleosome, a basic unit of chromatin, and alters chromatin structure and dynamics. In this study, we performed structural and biochemical analysis to understand the nucleosome binding by p300. Crosslinking mass spectrometry suggests that the p300 catalytic core binds to nucleosomes in multiple binding forms to acetylate different histone tails.

2022-06-29 | PXD033804 | JPOST Repository

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Project description:Nucleosome structure directly influences gene transcription. However, the function of each histone residue remains largely unknown. Here we profiled gene expression changes upon the mutation of individual residues of histone H3 and H4. Histone residues grouped by expression change similarity displayed overall structural relevance. This regulatory functional map of the core histones led to novel findings. First, the residues specific to each histone family tend to be more influential than those commonly found among different histones. Second, unlike histone acetylations, H3K4 trimethylation does not appear to be prerequisite for gene activation. Third, H3Q5 has been newly identified for its putative interactions with many chromatin regulators for transcription control. Lastly, the nucleosome lateral surface seems to play a key role through interactions with the surrounding DNA. Remarkably, we discovered a novel role for H3K56 in chromatin dynamics. The deletion of this residue, but not the alteration of acetylation states, caused a genome-wide decrease in nucleosome mobility and stabilized nucleosome positioning near transcription start and end sites. Occupying the DNA entry/exit site, H3K56 is thought to modulate nucleosome sliding along DNA. Taken together, genomics approaches such as microarray and deep sequencing prove valuable for mapping the function of histone residues. Microarray analysis was performed for 123 histone mutants and four wild-types as two reaplications of H3 and H4 of Saccharomyces ceravisiae.

2012-12-05 | E-GEOD-29059 | biostudies-arrayexpress

Chromosomal organization and genic expression in Apicomplexan parasites is critically dictated by a versatile acetylation-methylation switch at K31 on the lateral surface of histone H4

Project description:A striking unusual genome architecture characterizes the two related human parasitic pathogens Plasmodium falciparum and Toxoplasma gondii. A major fraction of the bulk parasite genome is packaged as transcriptionally permissive euchromatin with few loci embedded in silenced heterochromatin. Primary chromatin shapers include histone modifications at the nucleosome lateral surface close to the DNA but their mode of action remains unclear. We identify versatile modifications at Lys31 within the globular domain of histone H4 as key determinants of genome organization and expression in Apicomplexa. H4K31 acetylation promotes a relaxed chromatin state at the promoter of active genes through nucleosome disassembly in both parasites. In contrast, monomethylated H4K31 is enriched in the core body of Toxoplasma active genes but inversely correlates with transcription while being astonishingly enriched at transcriptionally inactive pericentromeric heterochromatin in Plasmodium. This is the first evidence for a methylated residue of H4 associating with transcriptional regulation likely by reducing histone turnover hence slowing RNA polymerase progression across transcribed loci.

2017-06-17 | GSE98806 | GEO

The histone acetylation module and histone chaperone in the Arabidopsis NuB4 complex have synergistic effect on chromatin accessibility (ATAC-Seq)

Project description:Although the conserved type B histone acetyltransferase is known to regulate both cytoplasmic histone acetylation and nuclear nucleosome assembly, the coordination between the dual functions remains poorly understood. Our study revealed that the Arabidopsis thaliana type B histone acetyltransferase HAG2 interactions with the histone chaperones MSI2, MSI3, and NASP, as well as histones H3 and H4, resulting in the formation of a conserved NuB4 complex. Within this complex, HAG2, MSI2, and MSI3 constitute a histone acetylation module that acetylates newly synthesized histone H4 at lysine 5 and 12 sites in the cytoplasm. This module collaborates with NASP to maintain the abundance of H3 and H4 proteins in the cytoplasm, but it is not necessary for nucleosome assembly in the nucleus, which differs from the role of NuB4 complexes in other eukaryotes. Furthermore, we found that, within the nucleus, the collaborative actions of the histone acetylation module and NASP enhance chromatin accessibility near the transcription start sites of protein-coding genes, while showing a negative impact on chromatin accessibility near the transcription termination sites. This suggests that the Arabidopsis NuB4 complex is responsible for modulating chromatin accessibility across the entire genome, highlighting a plant-specific function of the NuB4 complex.

2024-10-25 | GSE259413 | GEO

The histone acetylation module and histone chaperone in the Arabidopsis NuB4 complex have synergistic effect on chromatin accessibility (RNA-Seq)

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The histone acetylation module and histone chaperone in the Arabidopsis NuB4 complex have synergistic effect on chromatin accessibility (ChIP-Seq)

2024-10-25 | GSE259414 | GEO

Epigenetic mechanisms to propagate histone acetylation by p300/CBP

Project description:Histone acetylation is important for the activation of gene transcription but little is known about its direct ‘read/write’ mechanisms. Here, we report cryo-electron microscopy structures in which a p300/CBP multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTac via the bromodomain pocket responsible for ‘reading’, but also interacted with the DNA minor grooves via the outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 ‘writes’ by ‘reading’ H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP ‘replicates’ histone NT acetylation within the H3-H4 tetramer to inherit epigenetic storage, and ‘transcribes’ it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.

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