Genome-wide H3K27 trimethylation patterns when AMPKa1 and AMPKa2 (AMPKa DKO) were deleted in mouse embryonic fibroblast cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE97734 | GEO | 2017/12/15
SECONDARY ACCESSION(S): PRJNA382781
REPOSITORIES: GEO
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Project description:The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased histone H3K27 trimethylation (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) also plays an important role in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is identified as a new ATM kinase target, and its S734 phosphorylation reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3in ATM deficiency. ChIP-sequencing shows a significant increase in H3K27me3 ‘marks’ and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle re-entry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescues Purkinje cell degeneration and behavioral abnormalities in Atm / mice, demonstrating that EZH2-mediated H3K27me3 is another key factor in A-T neurodegeneration. Two samples each were run of brain total RNA from Atm+/+ and Atm-/- mice.
2013-10-25 | E-GEOD-50951 | biostudies-arrayexpress
Project description:ChIP-seq of H3K27 trimethylation in sciatic nerve H3K27me3 ChIP-Seq with corresponding input
2015-04-01 | E-GEOD-64260 | biostudies-arrayexpress
Project description:The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased histone H3K27 trimethylation (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) also plays an important role in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is identified as a new ATM kinase target, and its S734 phosphorylation reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3in ATM deficiency. ChIP-sequencing shows a significant increase in H3K27me3 ‘marks’ and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle re-entry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescues Purkinje cell degeneration and behavioral abnormalities in Atm / mice, demonstrating that EZH2-mediated H3K27me3 is another key factor in A-T neurodegeneration.
2013-10-25 | GSE50951 | GEO
Project description:Trimethylation of histone H3 lysine 27 (H3K27me3) plays a critical role in regulating gene expression during plant and animal development. We characterized the genome-wide distribution of H3K27me3 in five developmentally distinct tissues in maize plants of two genetic backgrounds, B73 and Mo17, representatives of two distinct heterotic groups. There are numerous differences in the distribution of H3K27me3 among tissues. In contrast, we found the distribution of H3K27me3 among the two genetic backgrounds to be quite similar. The tissue-specific patterns of H3K27me3 are often associated with differences in gene expression among the tissues and most of the imprinted genes that are expressed solely from the paternal allele in endosperm are targets of H3K27me3. Many maize genes with important developmental roles, including numerous genes encoding putative transcription factors, are modified with H3K27me3 in at least one of the tissues that were profiled. A comparison of the H3K27me3 targets in rice, maize, and Arabidopsis provided evidence for conservation of the H3K27me3 targets among plant species. However, there was limited evidence for conserved targeting of H3K27me3 in the two maize subgenomes derived from whole genome duplication. Genomic profiling of H3K27me3 in loss-of-function mutant stocks for Mez2 and Mez3, two of the three putative H3K27me3 methyltranferases present in the maize genome, suggests partial redundancy of this gene family for maintaining H3K27me3 patterns. Only a portion of the targets of H3K27me3 requires Mez2 and/or Mez3 and there was limited evidence for functional consequences of H3K27me3 at these targets. This study provides a catalogue of 6,337 genes that are marked by H3K27me3 in five maize tissues. B73 tissues for h3k27 analysis: Samples are replicated in triplicate with antibody pulldown (IP) and control genomic DNA (input) channels. histone modification mutants for h3k27 analysis: Samples are replicated in triplicate with antibody pulldown (IP) and control genomic DNA (input) channels. Mo17 tissues for h3k27 analysis: Samples contain antibody pulldown (IP) and control genomic DNA (input) channels.
2013-02-20 | E-GEOD-39456 | biostudies-arrayexpress
Project description:Trimethylation of histone H3 lysine 27 (H3K27me3) plays a critical role in regulating gene expression during plant and animal development. We characterized the genome-wide distribution of H3K27me3 in five developmentally distinct tissues in maize plants of two genetic backgrounds, B73 and Mo17, representatives of two distinct heterotic groups. There are numerous differences in the distribution of H3K27me3 among tissues. In contrast, we found the distribution of H3K27me3 among the two genetic backgrounds to be quite similar. The tissue-specific patterns of H3K27me3 are often associated with differences in gene expression among the tissues and most of the imprinted genes that are expressed solely from the paternal allele in endosperm are targets of H3K27me3. Many maize genes with important developmental roles, including numerous genes encoding putative transcription factors, are modified with H3K27me3 in at least one of the tissues that were profiled. A comparison of the H3K27me3 targets in rice, maize, and Arabidopsis provided evidence for conservation of the H3K27me3 targets among plant species. However, there was limited evidence for conserved targeting of H3K27me3 in the two maize subgenomes derived from whole genome duplication. Genomic profiling of H3K27me3 in loss-of-function mutant stocks for Mez2 and Mez3, two of the three putative H3K27me3 methyltranferases present in the maize genome, suggests partial redundancy of this gene family for maintaining H3K27me3 patterns. Only a portion of the targets of H3K27me3 requires Mez2 and/or Mez3 and there was limited evidence for functional consequences of H3K27me3 at these targets. This study provides a catalogue of 6,337 genes that are marked by H3K27me3 in five maize tissues.
2013-02-20 | GSE39456 | GEO
Project description:Metformin has been used for the treatment of type II diabetes mellitus for decades. Recently, used of metformin in the therapy of diverse human cancer types has received widespread attention, while the underlying mechanisms have been not fully elucidated. In the current study, 5-ethynyl-20-deoxyuridine assay to detect cell proliferation, flow cytometry to detect apoptosis, scratch wound healing and Transwell migration assay to detect cell migration capacity. The current study reported that metformin inhibited cell proliferation and migration, and promoted apoptosis in ovarian cancer cells, particularly under normoglycemic conditions in vitro. Metformin treatment significantly promoted the phosphorylation of AMP-activated protein kinase (AMPK), and reduced histone H3 lysine 27 trimethylation (H3K27me3) and polycomb repressor complex 2 (PRC2) levels. Additionally, overexpression of EZH2 to increase H3K27me3 abrogated the effect of metformin on the cell proliferation, migration and apoptosis in SKOV3 and ES2 cells. Similar to metformin, another AMPK agonist, 2-deoxy-D-glucose, reduced the H3K27me3 level and PRC2 expression. In cells pretreated with Compound C, an AMPK inhibitor, metformin was not able to induce AMPK phosphorylation or reduce H3K27me3. Metformin-mediated AMPK activation and H3K27me3 inhibition were more robust in cells exposed to low glucose (5.5 mM) compared with those exposed to high glucose (25 mM). These findings implicate H3K27me3 repression mediated by AMPK phosphorylation in the antitumor effect of metformin in ovarian cancer, indicating that metformin alters epigenetic modifications by targeting PRC2 and supports the use of metformin in treatment of patients with epithelial ovarian cancer without diabetes.
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Project description:During growth of multicellular organisms, identities of stem cells and differentiated cells need to be maintained. Cell fate is epigenetically controlled by the conserved Polycomb-group (Pc-G) proteins that repress their target genes by catalyzing histone H3 lysine 27 trimethylation (H3K27me3). Although H3K27me3 is associated with mitotically stable gene repression, a large fraction of H3K27me3 target genes are tissue-specifically activated during differentiation processes. However, in plants it is currently unclear whether H3K27me3 is already present in undifferentiated cells and dynamically regulated to permit tissue-specific gene repression or activation. We used whole-genome tiling arrays to identify the H3K27me3 target genes in undifferentiated cells of the shoot apical meristem and in differentiated leaf cells. Hundreds of genes gain or lose H3K27me3 upon differentiation, demonstrating dynamic regulation of an epigenetic modification in plants. H3K27me3 is correlated with gene repression, and its release preferentially results in tissue-specific gene activation, both during differentiation and in Pc-G mutants. We further reveal meristem- and leaf-specific targeting of individual gene families including known but also likely novel regulators of differentiation and stem cell regulation. Interestingly, H3K27me3 directly represses only specific transcription factor families, but indirectly activates others through H3K27me3-mediated silencing of microRNA genes. Furthermore, H3K27me3 targeting of genes involved in biosynthesis, transport, perception, and signal transduction of the phytohormone auxin demonstrates control of an entire signaling pathway. Based on these and previous analyses, we propose that H3K27me3 is one of the major determinants of tissue-specific expression patterns in plants, which restricts expression of its direct targets and promotes gene expression indirectly by repressing miRNA genes.
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Project description:Epigenetic modifications in the form of altered DNA or histone methylation can influence gene expression patterns critical for neoplastic initiation and progression. The fact that abnormal gene expression can be driven by epigenetic alterations led us to examine the correlation between DNA methylation, trimethylation of histone 3 lysine 9 (H3K9me3) and lysine 27 (H3K27me3), and gene expression in esophageal adenocarcinoma (EAC). Using genome-wide approaches (chromatin immunoprecipitation/sequencing (ChIP-Seq) and methylation arrays), we identified gene targets that were enriched with the chromatin-repressive marks H3K9me3, H3K27me3, and/or DNA hypermethylation across patients with EAC. Using RNA-Seq, we found genes involved in cellular morphology and movement, epithelial cell differentiation, epithelial junction signaling, as well as genes involved in epithelial-mesenchymal transition (EMT) were down-regulated in patients with poorly differentiated EAC. Additionally, comparative analyses of ChIP-Seq, DNA methylation, and RNA-Seq data allowed us to identify a group of genes downregulated in EAC is associated with aberrant H3K27me3 enrichment or a combination of H3K27me3 and DNA hypermethylation in the poorly differentiated EAC cases. Furthermore, by comparison to TCGA data sets, H3K27me3 enrichment is associated with aberrant DNA methylation across numerous EAC cases, suggesting that dysregulation of H3K27me3 and DNA methylation is crucial in the pathogenesis of EAC.
2019-02-01 | GSE94544 | GEO
Project description:Epigenetic modifications in the form of altered DNA or histone methylation can influence gene expression patterns critical for neoplastic initiation and progression. The fact that abnormal gene expression can be driven by epigenetic alterations led us to examine the correlation between DNA methylation, trimethylation of histone 3 lysine 9 (H3K9me3) and lysine 27 (H3K27me3), and gene expression in esophageal adenocarcinoma (EAC). Using genome-wide approaches (chromatin immunoprecipitation/sequencing (ChIP-Seq) and methylation arrays), we identified gene targets that were enriched with the chromatin-repressive marks H3K9me3, H3K27me3, and/or DNA hypermethylation across patients with EAC. Using RNA-Seq, we found genes involved in cellular morphology and movement, epithelial cell differentiation, epithelial junction signaling, as well as genes involved in epithelial-mesenchymal transition (EMT) were down-regulated in patients with poorly differentiated EAC. Additionally, comparative analyses of ChIP-Seq, DNA methylation, and RNA-Seq data allowed us to identify a group of genes downregulated in EAC is associated with aberrant H3K27me3 enrichment or a combination of H3K27me3 and DNA hypermethylation in the poorly differentiated EAC cases. Furthermore, by comparison to TCGA data sets, H3K27me3 enrichment is associated with aberrant DNA methylation across numerous EAC cases, suggesting that dysregulation of H3K27me3 and DNA methylation is crucial in the pathogenesis of EAC.
2019-02-01 | GSE94487 | GEO
Project description:The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased trimethylation of histone H3 on Lys27 (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) is also important in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is a new ATM kinase target, and ATM-mediated phosphorylation of EZH2 on Ser734 reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3 in ATM deficiency. Chromatin immunoprecipitation and sequencing showed an increase in H3K27me3 'marks' and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle reentry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescued Purkinje cell degeneration and behavioral abnormalities in Atm(-/-) mice, demonstrating that EZH2 hyperactivity is another key factor in A-T neurodegeneration.
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