Histone H4 N-terminal tail mutants
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE2324 | GEO | 2005/03/05
SECONDARY ACCESSION(S): PRJNA91693
REPOSITORIES: GEO
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Project description:A series of yeast carrying K->R mutations in the histone H4 N-terminal tail were profiled by gene expression array in mid-log phase.
2010-06-10 | E-GEOD-2324 | biostudies-arrayexpress
Project description:Yeast strain containing either a histone H4 wild type or K91A allele was grown in YPD to mid-log phase and harvested. Three replicates of each allele were performed Keywords: repeat sample
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Project description:ISWI-family nucleosome remodeling enzymes need the histone H4 N-terminal tail to mobilize nucleosomes. Here we mapped the H4-tail binding pocket of ISWI. Surprisingly the binding site was adjacent to but not overlapping with the docking site of an auto-regulatory motif, AutoN, in the N-terminal region (NTR) of ISWI, indicating that AutoN does not act as a simple pseudosubstrate as suggested previously. Rather, AutoN cooperated with a hitherto uncharacterized motif, termed AcidicN, to confer H4-tail sensitivity and discriminate between DNA and nucleosomes. A third motif in the NTR, ppHSA, was functionally required in vivo and provided structural stability by clamping the NTR to Lobe 2 of the ATPase domain. This configuration is reminiscent of Chd1 even though Chd1 contains an unrelated NTR. Our results shed light on the intricate structural and functional regulation of ISWI by the NTR and uncover surprising parallels with Chd1. Elife. 2017 Jan 21;6. pii: e21477. doi: 10.7554/eLife.21477. [Epub ahead of print]
2017-02-02 | PXD005831 | Pride
Project description:Yeast strain containing either a histone H4 wild type or K91A allele was grown in YPD to mid-log phase and harvested. Three replicates of each allele were performed
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Project description:IκBs exert a principal function as cytoplasmic inhibitors of the NF-kB transcription factors. Additional functions for specific IκB homologues have also been described including their association to chromatin to directly regulate gene transcription. Phosphorylated and SUMOylated IκBα (pS-IκBα) specifically binds histones H2A and H4 in the stem and progenitor compartment of skin and intestine, but the mechanisms that control the recruitment of nuclear pS-IκBα to the chromatin are largely unstudied. We here show thatserine 32-36 phosphorylation of IκBα favors its binding with nucleosomes and demonstrated that p-IκBαassociation to H4 is favored by acetylation at specific H4 lysine (K) residues. Acetylated N-terminal tail of H4 is lost during intestinal cell differentiation due to histone cleavage at amino acids 17-19 by the action of trypsin or chymotrypsin, which interferes p-IκBα association to chromatin. Paradoxically, pharmacologic or genetic inhibition of trypsin and chymotrypsin activity in HT29 cells increased p-IκBα chromatin binding, associated to impaired goblet cell differentiation, which was comparable to IκBα deletion. Together our results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular base for the restricted nuclear distribution of p-IκBα at specific stem cell compartments.
2021-06-21 | GSE167087 | GEO
Project description:Oncohistone mutations are crucial drivers for tumorigenesis, but how a living organism responds to and governs the loss-of-function oncohistone remains unclear. Here, we generated a histone H2B triple knockout (3KO) strain in Caenorhabditis elegans, which decreased the embryonic H2B level, disrupted cell divisions, and caused animal sterility. Our genetic screens identified mutations defective in a histone H3-H4 chaperone UNC-85 as suppressors that recovered H2B 3KO fertility. We found that unc-85 mutations reduced chromatin H3-H4 levels and that inhibiting other H3-H4 chaperones or H3-H4 histones also rescued H2B 3KO sterility. The oncohistone H2BE76K mutation disrupts the H2B-H4 interface and causes nucleosome instability, and we showed that blocking H3-H4 chaperones restored cell division defects in C. elegans or human cells carrying H2BE76K. Thus, our results indicate that reducing chromatin H3-H4 rescues H2B loss and suggest that inhibiting H3-H4 chaperones may be a therapeutic strategy to treat cancers resulting from loss-of-function H2B oncohistone.
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Project description:Chromatin integrates extracellular signals to regulate gene expression and, therefore, tightly controls development. Mutations in histone genes, including H3.3 and H4, were recently identified in children with developmental disorders characterized by intellectual disability and dysmorphic facial features1–7. However, the mechanistic and functional roles of these de novo, heterozygous germline mutations remain largely unknown. Here, we focus on the histone H4 lysine 91 to arginine (H4K91R) or glutamine (H4K91Q) mutations located within the highly conserved core histone fold domain. Our findings demonstrate that H4K91 mutants form aberrant nuclear puncta in mouse embryonic stem cells (mESCs), as well as in differentiated neural cells in vitro and in vivo. Genome-wide analyses revealed that H4K91 mutants accumulate ectopically at H3.3 and H3K9me3-enriched heterochromatin regions. Mechanistically, H4K91 mutants demonstrated enhanced binding to histone H3 variant H3.3, and ablation of H3.3 or the H3.3-specific chaperone DAXX diminished the formation of H4 mutant puncta and enrichment at heterochromatin regions. Additionally, H4 mutant expression increased chromatin accessibility in mammalian cells. Phenotypically, H4 mutant mice exhibit reduced brain size and altered cortical neuron layers, reminiscent of microcephaly phenotypes observed in patients. Consistent with the altered brain development in vivo, the expression of H4 mutants alter developmental gene expression and accelerate pro-neural differentiation in cell culture models. Together, these studies reveal multiple concurrent pathogenic mechanisms of H4 mutants found in developmental disorders and further our understanding of how histone mutants regulate cell fate during development.
2023-10-19 | GSE231566 | GEO
Project description:Chromatin integrates extracellular signals to regulate gene expression and, therefore, tightly controls development. Mutations in histone genes, including H3.3 and H4, were recently identified in children with developmental disorders characterized by intellectual disability and dysmorphic facial features1–7. However, the mechanistic and functional roles of these de novo, heterozygous germline mutations remain largely unknown. Here, we focus on the histone H4 lysine 91 to arginine (H4K91R) or glutamine (H4K91Q) mutations located within the highly conserved core histone fold domain. Our findings demonstrate that H4K91 mutants form aberrant nuclear puncta in mouse embryonic stem cells (mESCs), as well as in differentiated neural cells in vitro and in vivo. Genome-wide analyses revealed that H4K91 mutants accumulate ectopically at H3.3 and H3K9me3-enriched heterochromatin regions. Mechanistically, H4K91 mutants demonstrated enhanced binding to histone H3 variant H3.3, and ablation of H3.3 or the H3.3-specific chaperone DAXX diminished the formation of H4 mutant puncta and enrichment at heterochromatin regions. Additionally, H4 mutant expression increased chromatin accessibility in mammalian cells. Phenotypically, H4 mutant mice exhibit reduced brain size and altered cortical neuron layers, reminiscent of microcephaly phenotypes observed in patients. Consistent with the altered brain development in vivo, the expression of H4 mutants alter developmental gene expression and accelerate pro-neural differentiation in cell culture models. Together, these studies reveal multiple concurrent pathogenic mechanisms of H4 mutants found in developmental disorders and further our understanding of how histone mutants regulate cell fate during development.
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