Transcriptional regulation by H3K122 acetylation in the lateral surface of the histone octamer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE35954 | GEO | 2013/02/14
SECONDARY ACCESSION(S): PRJNA151991
REPOSITORIES: GEO
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Project description:We characterize the acetylation of H3K122 for the first time. Towards this we mapped the genomic distribution of H3K122Ac, identified the enzyme introducing H3K122Ac, and addressed the functional contribution H3K122Ac to transcription. We found that H3K122Ac is associated with chromatin marks and genomic regions associated with active transcription and is catalysed by p300/CBP and can be regulated by estrogen signaling in MCF-7. Moreover H3K122Ac stimulates transcription as dermined by in vitro transcription assays ChIP seq study
2013-02-14 | E-GEOD-35954 | biostudies-arrayexpress
Project description:We report the acetylation of lysine residues in the globular domain of H3 (H3K64ac and H3K122ac) marks active gene promoters and also a subset of active enhancers in mouse embryonic stem cells (mESCs), human erythroleukemic cell line (K562). Moreover, we find a novel class of active functional enhancers in ESCs that are marked by H3K122ac but which lack H3K27ac. This work suggests that a more complex analysis of histone acetylation is required to identify enhancers than was previously considered. Examination of histone modifications in mouse ESCs (2 biological replicates) and K562 cells
2016-03-12 | E-GEOD-66023 | biostudies-arrayexpress
Project description:Histone post-translational modifications (PTMs) are key players in chromatin regulation. The recent identification of novel histone acylations raised important questions regarding their role in transcriptional regulation. In this study, we characterized the role of succinylation of H3K122 (H3K122succ), located on the lateral surface of the histone octamer, in transcription and in chromatin function. Using chromatin, site-specifically succinylated at H3K122, we found that the presence of H3K122succ is sufficient to stimulate transcription in vitro. In line with this H3K122succ was enriched on promoters of active genes in mammalian cells and enrichment levels scale with gene expression. Furthermore, we show that the p300 and CBP co-activators are H3K122 succinyltransferases and identify sirtuin 5 (SIRT5) as a new desuccinylase. By applying single molecule FRET assays we demonstrate a direct effect of H3K122succ on nucleosome stability indicating an important role for histone succinylation in modulating chromatin dynamics. Together, these data provide the first insights into the molecular mechanisms of H3K122succ in transcriptional regulation and they highlight a structural function for H3K122succ through direct perturbation of nucleosomes.
2021-02-01 | GSE152019 | GEO
Project description:We report the acetylation of lysine residues in the globular domain of H3 (H3K64ac and H3K122ac) marks active gene promoters and also a subset of active enhancers in mouse embryonic stem cells (mESCs), human erythroleukemic cell line (K562). Moreover, we find a novel class of active functional enhancers in ESCs that are marked by H3K122ac but which lack H3K27ac. This work suggests that a more complex analysis of histone acetylation is required to identify enhancers than was previously considered.
2016-03-12 | GSE66023 | GEO
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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Project description:This study investigates the interactions between two enzymes involved in regulating the protein tau’s PTMs: the kinase MARK2 and the acetyltransferase CBP. Western blot analysis revealed that CBP-mediated acetylation was increased in the absence of MARK2, indicating a possible negative feedback loop, where MARK2 is inhibiting CBP acetylation. In contrast, inactive MARK2 (MARK2-KR) was strongly acetylated in the presence of acetyl-CBP, consistent with the preferential CBP binding and targeting of the inactive MARK2 conformation. To determine the specific lysine residues in MARK2 that are subject to acetylation in the presence of CBP, we immunopurified MARK2-KR alone (as a control) and CBP-acetylated MARK2-KR. We analyzed the immunopurified MARK2-KR by mass spectrometry-based proteomics to determine differential acetyl and phosphorylation sites.
2022-06-09 | PXD030937 | Pride
Project description:CBP/p300 are transcription co-activators whose binding is a signature of enhancers, cis-regulatory elements that control patterns of gene expression in multicellular organisms. Active enhancers produce bi-directional enhancer RNAs (eRNAs) and display CBP/p300 dependent histone acetylation. Here, we demonstrate that CBP binds directly to RNAs in vivo and in vitro. RNAs bound to CBP in vivo include a large number of eRNAs. Using steady-state histone acetyltransferase (HAT) assays we show that an RNA binding region in the HAT domain of CBP—a regulatory motif unique to CBP/p300—allows RNA to stimulate CBP’s HAT activity. At enhancers where CBP interacts with eRNAs, stimulation manifests in RNA-dependent changes in the histone acetylation mediated by CBP, such as H3K27ac, and by corresponding changes in gene expression. By interacting directly with CBP, eRNAs contribute to the unique chromatin structure at active enhancers, which in turn is required for regulation of target genes.
2017-01-12 | GSE75684 | GEO
Project description:Global changes in chromatin organization and the cessation of transcription during mitosis are thought to challenge the resumption of appropriate transcription patterns following mitosis. The acetyl-lysine binding protein BRD4 has been previously suggested to function as a transcriptional “bookmark” on mitotic chromatin. Here, genome-wide location analysis of BRD4 in erythroid cells, combined with novel data normalization and peak characterization approaches, reveals that BRD4 widely occupies mitotic chromatin. However, removal of BRD4 from mitotic chromatin does not impair post-mitotic activation of transcription. Additionally, histone mass spectrometry reveals global preservation of most posttranslational modifications (PTMs) during mitosis. In particular, H3K14ac, H3K27ac, H3K122ac, and H4K16ac widely mark mitotic chromatin, especially at lineage-specific genes, and predict BRD4 mitotic binding genome wide. Therefore, BRD4 is likely not a mitotic bookmark but only a “passenger”. Instead, mitotic histone acetylation patterns may constitute the actual bookmarks that restore lineage-specific transcription patterns after mitosis.
2019-04-10 | GSE128161 | GEO
Project description:Global changes in chromatin organization and the cessation of transcription during mitosis are thought to challenge the resumption of appropriate transcription patterns following mitosis. The acetyl-lysine binding protein BRD4 has been previously suggested to function as a transcriptional “bookmark” on mitotic chromatin. Here, genome-wide location analysis of BRD4 in erythroid cells, combined with novel data normalization and peak characterization approaches, reveals that BRD4 widely occupies mitotic chromatin. However, removal of BRD4 from mitotic chromatin does not impair post-mitotic activation of transcription. Additionally, histone mass spectrometry reveals global preservation of most posttranslational modifications (PTMs) during mitosis. In particular, H3K14ac, H3K27ac, H3K122ac, and H4K16ac widely mark mitotic chromatin, especially at lineage-specific genes, and predict BRD4 mitotic binding genome wide. Therefore, BRD4 is likely not a mitotic bookmark but only a “passenger”. Instead, mitotic histone acetylation patterns may constitute the actual bookmarks that restore lineage-specific transcription patterns after mitosis.
2019-04-10 | GSE128150 | GEO
Project description:It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However in vivo transcription factors find their binding sites while confronted with a large excess of low affinity degenerate motifs. Here we show, using the melanoma lineage survival oncogene MITF as a model, that low affinity binding sites act as a competitive reservoir in vivo from which TFs are released by MAPK-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently a low DNA-binding affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high affinity, non-acetylatable mutant does neither. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide titration and couples BRAF to tumorigenesis. Our results further suggest that genomic titration regulated by p300/CBP-mediated acetylation will represent a common mechanism to control TF availability.
2020-06-11 | GSE137522 | GEO