MacroH2A1 ChIP-seq from IMR90 human primary lung fibroblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Matthew Gamble
PROVIDER: E-GEOD-54845 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The histone variant macroH2A1 and the poly(ADP-ribose) polymerase PARP-1 both regulate gene transcription by modulating chromatin structure and function. Of the two macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, the former is often suppressed in cancer and has the unique ability to interact with poly(ADP-ribose). Using ChIP-seq in primary lung fibroblasts, we demonstrate that macroH2A1 is incorporated into either of two spatially and functionally distinct types of chromatin; the first is marked by H3 K27 trimethylation, while the second contains a set of nine histone acetylations. MacroH2A1-regulated genes are involved in cancer progression are specifically found in macroH2A1-containing acetylated chromatin. Through the recruitment of PARP-1, macroH2A1.1 promotes the acetylation of H2B K12 and K120 which plays a key role in the regulation of macroH2A1 target genes in primary cells. The macroH2A1/PARP-1 pathway regulating H2B K12 and K120 acetylation is disrupted in cancer cells, in part, explaining macroH2A1’s role in cancer suppression. Three biological replicates of RNA-seq from cells expressing shRNA directed against macroH2A1 or luciferase as a control
2014-09-15 | E-GEOD-54846 | biostudies-arrayexpress
Project description:The histone variant macroH2A1 and the poly(ADP-ribose) polymerase PARP-1 both regulate gene transcription by modulating chromatin structure and function. Of the two macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, the former is often suppressed in cancer and has the unique ability to interact with poly(ADP-ribose). Using ChIP-seq in primary lung fibroblasts, we demonstrate that macroH2A1 is incorporated into either of two spatially and functionally distinct types of chromatin; the first is marked by H3 K27 trimethylation, while the second contains a set of nine histone acetylations. MacroH2A1-regulated genes are involved in cancer progression are specifically found in macroH2A1-containing acetylated chromatin. Through the recruitment of PARP-1, macroH2A1.1 promotes the acetylation of H2B K12 and K120 which plays a key role in the regulation of macroH2A1 target genes in primary cells. The macroH2A1/PARP-1 pathway regulating H2B K12 and K120 acetylation is disrupted in cancer cells, in part, explaining macroH2A1’s role in cancer suppression.
2014-09-15 | GSE54846 | GEO
Project description:The histone variant macroH2A1 and the poly(ADP-ribose) polymerase PARP-1 both regulate gene transcription by modulating chromatin structure and function. Of the two macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, the former is often suppressed in cancer and has the unique ability to interact with poly(ADP-ribose). Using ChIP-seq in primary lung fibroblasts, we demonstrate that macroH2A1 is incorporated into either of two spatially and functionally distinct types of chromatin; the first is marked by H3 K27 trimethylation, while the second contains a set of nine histone acetylations. MacroH2A1-regulated genes are involved in cancer progression are specifically found in macroH2A1-containing acetylated chromatin. Through the recruitment of PARP-1, macroH2A1.1 promotes the acetylation of H2B K12 and K120 which plays a key role in the regulation of macroH2A1 target genes in primary cells. The macroH2A1/PARP-1 pathway regulating H2B K12 and K120 acetylation is disrupted in cancer cells, in part, explaining macroH2A1’s role in cancer suppression.
2014-09-15 | GSE54845 | GEO
Project description:Non-small cell lung cancer (NSCLC) is often treated with cisplatin (CDDP). Here, we report that two distinct poly(ADP-ribose) polymerase (PARP) inhibitors exhibited a hyperadditive combination effect with CDDP to kill NSCLC cells. A majority of CDDP-resistant cell lines and clones exhibited constitutively increased PARP expression and enzymatic activity. Cells with hyperactivated PARP initiated a DNA damage response and the intrinsic pathway of apoptosis in response to pharmacological PARP inhibition or PARP1-targeting siRNAs. Transcriptome analysis depicted an unsupervised hierarchical clustering of NSCLC cells and CDDP resistant counterparts regarding to their response to PARP inhibitors. PARP-overexpressing tumors displayed elevated levels of intracellular poly(ADP-ribose) (PAR), which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP expression itself. Thus, CDDP-resistant cancer cells develop a dependency to PARP, becoming susceptible to PARP inhibitor-induced apoptosis.
2013-10-31 | E-MTAB-1353 | biostudies-arrayexpress
Project description:Poly(ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose) glycohydrolase (PARG) are enzymes that modify target proteins in the nucleus by the addition and removal, respectively, of ADP-ribose polymers. Although a role for PARP-1 in gene regulation has been well established, the role of PARG is less clear. To investigate how PARP-1 and PARG coordinately regulate global patterns of gene expression, we used short hairpin RNAs (shRNAs) to stably knockdown PARP-1 or PARG in MCF-7 cells, followed by expression microarray analyses.
2009-10-23 | GSE12952 | GEO
Project description:MacroH2A1 is a histone variant that is enriched on the inactive X chromosome (Xi) in mammals and is postulated to play an important, but unknown, role in the repression of gene expression. Here we show that although macroH2A1 marks repressed autosomal chromatin, it positively regulates transcription when located in the transcribed regions of many target genes. We used chromatin immunoprecipitation coupled with tiling microarrays (ChIP-chip) to determine the genomic localization of macroH2A1 in IMR90 human primary lung fibroblasts and MCF-7 breast cancer cells. The patterns of macroH2A1 deposition are largely similar across the autosomes of both cell lines. Our studies revealed a genomic localization pattern unique among histone variants, namely the occupation by macroH2A1 of large chromatin domains (>500 kb in some cases) that contain repressive chromatin marks (e.g., histone H3 lysine 27 trimethylation). The boundaries of macroH2A1-containing domains tend to occur in promoter proximal regions. Not all promoters, however, serve as macroH2A1 boundaries; many macroH2A1-containing chromatin domains invade the transcribed regions of genes whose products play key roles in development and cell-cell signaling. Surprisingly, the expression of many of these genes is positively regulated by macroH2A1. MacroH2A1 also plays a role in augmenting signal-regulated transcription, specifically for genes responsive to serum starvation. Collectively, our results document an unexpected role for macroH2A1 in the escape from heterochromatin-associated silencing and the enhancement of autosomal gene transcription. Two macroH2A1 ChIP-chip biological replicates from IMR90 human embryonic lung fibroblasts are included.
2010-06-20 | E-GEOD-18633 | biostudies-arrayexpress
Project description:The macro domain of the histone variant macroH2A1.1 is an evolutionary conserved ADP ribose-binding module of unknown physiological function. We demonstrate that during myogenic differentiation alternative splicing switches the expression of macroH2A1 from the non-ADP ribose binding to the binding isoform. While differentiation commitment is normal in cells lacking macroH2A1.1, we observe two phenotypes: diminished cell fusion correlating with reduced expression of adhesion and migration genes and reduced mitochondrial capacity. While the integrity of the ADP ribose-binding pocket is dispensable for gene regulation and fusion, it is critical to sustain optimal mitochondrial fatty acid oxidation. Rescue experiments using a pharmacological PARP-1 inhibitor and metabolomics support the idea that loss of macroH2A1.1 leads to PARP-1 activation and accelerated NAD+ consumption. As a consequence, the level of nicotinamide mononucleotide, the key metabolite for mitochondrial NAD+ pool regeneration, is reduced and sirtuins fail to maintain mitochondrial proteins in their hypoacetylated and active form. Our results support the idea that chromatin states containing the histone variant macroH2A1.1 contribute to optimal mitochondrial oxidative capacity by channeling the consumption of NAD+ from the nucleus to mitochondria in a manner largely independent on transcriptional regulation.
2017-08-18 | GSE70015 | GEO
Project description:The macro domain of the histone variant macroH2A1.1 is an evolutionary conserved ADP ribose-binding module of unknown physiological function. We demonstrate that during myogenic differentiation alternative splicing switches the expression of macroH2A1 from the non-ADP ribose binding to the binding isoform. While differentiation commitment is normal in cells lacking macroH2A1.1, we observe two phenotypes: diminished cell fusion correlating with reduced expression of adhesion and migration genes and reduced mitochondrial capacity. While the integrity of the ADP ribose-binding pocket is dispensable for gene regulation and fusion, it is critical to sustain optimal mitochondrial fatty acid oxidation. Rescue experiments using a pharmacological PARP-1 inhibitor and metabolomics support the idea that loss of macroH2A1.1 leads to PARP-1 activation and accelerated NAD+ consumption. As a consequence, the level of nicotinamide mononucleotide, the key metabolite for mitochondrial NAD+ pool regeneration, is reduced and sirtuins fail to maintain mitochondrial proteins in their hypoacetylated and active form. Our results support the idea that chromatin states containing the histone variant macroH2A1.1 contribute to optimal mitochondrial oxidative capacity by channeling the consumption of NAD+ from the nucleus to mitochondria in a manner largely independent on transcriptional regulation.
2017-08-18 | GSE78256 | GEO
Project description:We produced a genome-wide map of the distribution of macroH2A1 histone variants in mouse liver chromatin using high-throughput sequencing of DNA from macroH2A1 nucleosomes. Although macroH2A1 nucleosomes are widely distributed across the genome, their local concentration varies over a range of 100-fold or more. The transcribed regions of most active genes are depleted of macroH2A1, with many showing depletion of 3-fold or more. The inactive X chromosome appears to have relatively uniform macroH2A1 enrichment that averages approximately 3.9-fold, but most genes that are known to escape from X inactivation do not show this enrichment. We used macroH2A1 depletion to identify additional genes that escape X inactivation, but overall, our map supports the idea that relatively few genes escape in the mouse. The map also helped identify genes that appear to be direct targets of macroH2A1-mediated repression. MacroH2A1 nucleosomes were purified from female mouse liver chromatin by thiol-affinity chromatography (Mol. Cell Biol. 26, 4410 (2006)) and their distribution was compared to that of the bulk nucleosomes used as the starting material for the purification. Nucleosomal DNA from two independent preparations was pooled and mononucleosomal DNA was prepared from both macroH2A1 and starting material nucleosomes. Each preparation used 8 to 10 livers from 8 to 10 week old female mice. For the relative macroH2A1 content file (see supplementary file), we used tools in the rna-seq workflow of Partek Genomics Suite (version 6.5b, 6.09.0806, Partek Inc.) to calculate the relative macroH2A1 content of individual genes. This program counts and normalizes hits in predefined regions specified in a refFlat file. The gene list was the Mouse build 8 version of refFlat.txt obtained from the UCSC Genome site. All exon information was stripped from the refFlat.txt file, which left only the start and stop sites for the genes. Normalized RPKM (reads per kilobase per million reads) values were compared to calculate fold change and FDR-adjusted p-values for each transcript.
2010-11-10 | E-GEOD-18963 | biostudies-arrayexpress
Project description:Reward-related memory is an important factor in cocaine seeking. One necessary signaling mechanism for long-term memory formation is the activation of poly(ADP-ribose) polymerase-1 (PARP-1), via poly(ADP-ribosyl)ation. We demonstrate herein that auto-poly(ADP-ribosyl)ation of activated PARP-1 was significantly pronounced during retrieval of cocaine-associated contextual memory, in the central amygdala (CeA) of rats expressing cocaine-conditioned place preference (CPP). Intra-CeA pharmacological and shRNA depletion of PARP-1 activity during cocaine-associated memory retrieval abolished CPP. In contrast, PARP-1 inhibition after memory retrieval did not affect CPP reconsolidation process and subsequent retrievals. Chromatin Immuoprecipitation (ChIP) sequencing revealed that PARP-1 binding in the CeA is highly enriched in genes involved in neuronal signaling. We identified amongst PARP targets in CeA a single gene, yet uncharacterized and encoding a putative transposase inhibitor, at which PARP-1 enrichment dramatically increases during cocaine-associated memory retrieval and positively correlates with CPP. Our findings have important implications for understanding drug-related behaviors, and suggest possible future therapeutic targets for drug abuse. 4 samples, each is pooled central amygdalae tissues collected from 2 rats. Rats were trained for cocaine-conditioned place-preference (CPP), tissues were harvested immediately following cocaine-CPP retrieval. Three groups of rats were used: high cocaine CPP, low cocaine CPP and control saline only trained rats.
2016-06-25 | E-GEOD-83718 | biostudies-arrayexpress