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RNA-seq from control and macroH2A1-depleted IMR90 primary human lung fibroblasts

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54846 | GEO | 2014/09/15

SECONDARY ACCESSION(S): PRJNA237809

REPOSITORIES: GEO

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RNA-seq from control and macroH2A1-depleted IMR90 primary human lung fibroblasts

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

MacroH2A1 ChIP-seq from IMR90 human primary lung fibroblasts

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 macroH2A1M-bM-^@M-^Ys role in cancer suppression. Two biological replicates of the macroH2A1 ChIP and two corresponding input samples were sequenced

2014-09-15 | E-GEOD-54845 | biostudies-arrayexpress

MacroH2A1 ChIP-seq from IMR90 human primary lung fibroblasts

2014-09-15 | GSE54845 | GEO

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

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

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

2017-08-18 | GSE70015 | GEO

IGR_Michels_PARP

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

Expression Analysis Upon PARP-1 or PARG Knockdown in MCF-7 Cells

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

Depletion of PARP-2 in C2C12 cells

Project description:Poly(ADP-ribose) polymerase-2 (PARP-2) is acknowledged as a DNA repair enzyme; however, recently metabolic properties had been attributed to it. Hereby, we examined the metabolic consequences of PARP-2 ablation in skeletal muscle.

2020-12-18 | GSE108737 | GEO

Phase I study of Veliparib in combination with Cisplatin and Vinorelbine for patients with advanced triple-negative breast cancer (TNBC) and/or BRCA mutation-associated breast cancer

Project description:PURPOSE: Preclinically, cisplatin is synergistic with vinorelbine and the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib, and has anti-neoplastic activity in TNBC and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine. PATIENTS AND METHODS: A 3+3 dose escalation design evaluated veliparib administered BID for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1,8) every 21 days, for six to ten cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. Immunohistochemistry and gene expression profiling were performed to evaluate potential predictors of response. Thirty-nine samples were assessed, six samples were run as technical duplicates. Two of the samples had a high rate of missing probes and were excluded during the normalization/pre-processing. Each sample represents a pre- or post-treatment breast cancer specimen from individual patients.

2015-09-09 | E-GEOD-72795 | biostudies-arrayexpress

Cockayne syndrome group B deficiency reduces H3K9me3 chromatin remodeler SETDB1 and exacerbates cellular aging

Project description:Cockayne syndrome (CS) is an accelerated aging disorder, caused by mutations in the CSA or CSB genes. In CSB-deficient cells, poly (ADP ribose) polymerase (PARP) is persistently activated by unrepaired DNA damage and PARP consumes and depletes cellular nicotinamide adenine dinucleotide (NAD), which leads to mitochondrial dysfunction. Here, the distribution of poly (ADP ribose) (PAR) was determined in CSB-deficient cells using ADPr-ChAP (ADP ribose-chromatin affinity purification), and the results show striking enrichment of PAR at transcription start sites (TSS), depletion of heterochromatin, and downregulation of H3K9me3-specific methyltransferases SUV39H1 and SETDB1. Induced-expression of SETDB1 in CSB-deficient cells downregulated PAR and normalized mitochondrial function. The results suggest that defects in CSB are strongly associated with loss of heterochromatin, downregulation of SETDB1, increased PAR in highly-transcribed regions, and mitochondrial dysfunction.

2019-06-22 | GSE133176 | GEO

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