H3.3 depletion has a mild effect on the global transcriptome
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE84308 | GEO | 2017/02/10
SECONDARY ACCESSION(S): PRJNA328796
REPOSITORIES: GEO
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Project description:Background. The histone variant H3.3 plays key roles in regulating chromatin states and transcription. However, the role of endogenous H3.3 in mammalian cells and during development has been less thoroughly investigated. To address this gap, we report the production and phenotypic analysis of mice and cells with targeted disruption of the H3.3-encoding gene, H3f3b. Results. H3f3b KO mice exhibit a semi-lethal phenotype traceable at least in part to defective cell division and chromosome segregation. H3f3b KO cells have widespread ectopic CENP-A protein localization suggesting one possible mechanism for defective chromosome segregation. KO cells have abnormal karyotypes and cell cycle profiles as well. The transcriptome and euchromatin-related epigenome were moderately affected by loss of H3f3b in MEFs with ontology most notably pointing to changes in chromatin regulatory and histone coding genes. Reduced numbers of H3f3b KO mice survive to maturity and almost all survivors from both sexes are infertile. Conclusions. Taken together, our studies suggest that endogenous mammalian histone H3.3 has important roles in regulating chromatin and chromosome functions that in turn are important for cell division, genome integrity, and development. Examination of H3K9Ac and H3K4me3 in wild-type and H3.3 null MEFs
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Project description:Purpose: Pancreatic neuroendocrine tumors (PanNETs) have considerable malignant potential. Frequent somatic mutations and loss of DAXX protein expression have been frequently found in PanNETs. DAXX is known as a transcriptional repressor, however, molecular functions underlying loss of DAXX remain unclear in PanNETs. Experimental Design: We evaluated DAXX-knockdown (KD) and -knockout (KO) PanNET cells were analyzed for in vitro and vivo. The target genes were screened by microarray and chromatin immunoprecipitation (ChIP) assays for DAXX, histone H3.3 and H3K9me3 complex. Results: Microarray and ChIP analyses of DAXX-KD/KO identified 13 genes as the direct targets of DAXX transcriptional repressor. Among them, 5 genes were suppressed by DAXX/H3.3/H3K9me3 pathway. DAXX-KD/KO increased sphere forming activity, but it was suppressed by knockdown of the target gene. In xenograft models, tumorigenicity was significantly increased in DAXX-KO cells with high expression of the target. Clinically, higher recurrence was recognized in PanNETs with low expression of DAXX and high expression of the target than others. Conclusions: DAXX plays as a tumor suppressor and DAXX/H3.3 complex suppresses target genes by promoting H3K9me3 in PanNETs. DAXX and its target molecule might be effective biomarkers and therapeutic candidates.
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Project description:We found that the incorporation of histone H3 variant H3.3 was impaired and the accumulation of ZMYND11, which specifically binds to H3.3K36me3, was decreased in NSD2 KO MEFs. About H3K36me2, the average gene body profiles of H3K36me2 showed preferential enrichment of H3K36me2 at the promoter and first half of the genic regions. We examined H3K36me2 mark in super enhancer regions using the ROSE super enhancer prediction program and identified of the 519 super enhancer islands of H3K36me2 in WT MEFs the H3K36me2 signals were decreased in NSD2 KO MEFs
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Project description:Background. The histone variant H3.3 plays key roles in regulating chromatin states and transcription. However, the role of endogenous H3.3 in mammalian cells and during development has been less thoroughly investigated. To address this gap, we report the production and phenotypic analysis of mice and cells with targeted disruption of the H3.3-encoding gene, H3f3b. Results. H3f3b KO mice exhibit a semi-lethal phenotype traceable at least in part to defective cell division and chromosome segregation. H3f3b KO cells have widespread ectopic CENP-A protein localization suggesting one possible mechanism for defective chromosome segregation. KO cells have abnormal karyotypes and cell cycle profiles as well. The transcriptome and euchromatin-related epigenome were moderately affected by loss of H3f3b in MEFs with ontology most notably pointing to changes in chromatin regulatory and histone coding genes. Reduced numbers of H3f3b KO mice survive to maturity and almost all survivors from both sexes are infertile. Conclusions. Taken together, our studies suggest that endogenous mammalian histone H3.3 has important roles in regulating chromatin and chromosome functions that in turn are important for cell division, genome integrity, and development.
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Project description:In this study, we have uncovered novel proteolytic processing of the histone H3 tail in senescence models in primary fibroblasts and melanocytes. Cleavage of H3 tail occurs at two distinct residues and is mediated by Cathepsin L. We show that variant H3.3 is preferentially cleaved, and that cleaved histones are associated with chromatin and incorporated into nucleosomes. We also found that the histone chaperone ASF1a is required for chromatin incorporation of the cleaved histone species. Further, we show that overexpression of cleaved H3.3 induces a senescence program in fibroblasts in the absensence of oncogenic signaling. For the RNA-seq studies, growing IMR90 fibroblasts were compared to cells induced to senesce via oncogene activation or cleaved H3.3 overexpression. Growing controls consist of IMR90 cells infected with empty retroviral construct pBabe and grown under normal conditions for 13 days prior to RNA isolation. For oncogene-induced senescence samples, IMR90s carrying a tamoxifen-inducible H-RasV12 retroviral construct were induced to senesce by addition of 10nM tamoxifen to the media for 8 days. Finally, IMR90s were infected with a retroviral construct expressing the cleaved form of H3.3 with a C-terminal Flag tag. RNA samples form this group were isolated at days 3 (early) and 13 (late) post-infection. In all cases, total RNA samples were isolated using RNeasy kit (Qiagen) and prepared at the Icahn School of Medicine at Mount Sinai Genomics Core Facility for poly A library construction and sequencing on IlluminaHiSeq 2500.
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