The histone variant macroH2A modulates inflammatory response in cancer [HepG2]
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ABSTRACT:
PROVIDER: PRJNA679723 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13090271.fastq.gz | Fastqsanger.gz | |||
| SRR13090272.fastq.gz | Fastqsanger.gz | |||
| SRR13090273.fastq.gz | Fastqsanger.gz | |||
| SRR13090274.fastq.gz | Fastqsanger.gz | |||
| SRR13090275.fastq.gz | Fastqsanger.gz |
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Project description:The histone variant macroH2A modulates inflammatory response in cancer
| PRJNA679719 | ENA
Project description:The histone variant macroH2A modulates inflammatory response in cancer [xenograft]
| PRJNA679724 | ENA
Project description:MacroH2A histone variants have a major role in nuclear organization and large-scale 3D chromatin architecture. How these alterations impinge on the behaviour of cancer cells is not known. Here, we describe the analysis of the total macroH2A loss of function phenotype in a model of hepatoblastoma, the main childhood liver cancer. Performing transcriptomic analyses in xenografts and cell cultures, we find that macroH2A modulated the response of cancer cells to paracrine inflammatory signalling. Specifically, ablation of macroH2A ablation neutralized the induction of a large subset of genes by TNFα and led to the hyperactivation of another subset of genes. Among the top macroH2A-sensitive genes we find the cancer-related gene DKK1 . Depletion of macroH2A rendered the DKK1 gene hypersensitive to TNFα signalling boosting the secretion of DKK1 protein. On the gene regulation level, this was mediated by an alteration of the local chromatin structure and facilitated activation of distal enhancer elements. The study of human samples of hepatoblastoma showed that DKK1 is strongly upregulated in tumors and associated with poor patient outcome. Taken together our results suggest that the regulation of 3D chromatin architecture by macroH2A histone variants has a central role in the response and regulation of paracrine signalling that might be relevant for the interaction of cancers with immune cells and other cells in their microenvironment.
2022-09-20 | GSE161857 | GEO
Project description:The histone variant macroH2A modulates inflammatory response in cancer [UMI-4C]
| PRJNA840922 | ENA
Project description:MacroH2A histone variants have a major role in nuclear organization and large-scale 3D chromatin architecture. How these alterations impinge on the behaviour of cancer cells is not known. Here, we describe the analysis of the total macroH2A loss of function phenotype in a model of hepatoblastoma, the main childhood liver cancer. Performing transcriptomic analyses in xenografts and cell cultures, we find that macroH2A modulated the response of cancer cells to paracrine inflammatory signalling. Specifically, ablation of macroH2A ablation neutralized the induction of a large subset of genes by TNFα and led to the hyperactivation of another subset of genes. Among the top macroH2A-sensitive genes we find the cancer-related gene DKK1 . Depletion of macroH2A rendered the DKK1 gene hypersensitive to TNFα signalling boosting the secretion of DKK1 protein. On the gene regulation level, this was mediated by an alteration of the local chromatin structure and facilitated activation of distal enhancer elements. The study of human samples of hepatoblastoma showed that DKK1 is strongly upregulated in tumors and associated with poor patient outcome. Taken together our results suggest that the regulation of 3D chromatin architecture by macroH2A histone variants has a central role in the response and regulation of paracrine signalling that might be relevant for the interaction of cancers with immune cells and other cells in their microenvironment.
2022-09-20 | GSE161858 | GEO
Project description:MacroH2A histone variants have a major role in nuclear organization and large-scale 3D chromatin architecture. How these alterations impinge on the behaviour of cancer cells is not known. Here, we describe the analysis of the total macroH2A loss of function phenotype in a model of hepatoblastoma, the main childhood liver cancer. Performing transcriptomic analyses in xenografts and cell cultures, we find that macroH2A modulated the response of cancer cells to paracrine inflammatory signalling. Specifically, ablation of macroH2A ablation neutralized the induction of a large subset of genes by TNFα and led to the hyperactivation of another subset of genes. Among the top macroH2A-sensitive genes we find the cancer-related gene DKK1 . Depletion of macroH2A rendered the DKK1 gene hypersensitive to TNFα signalling boosting the secretion of DKK1 protein. On the gene regulation level, this was mediated by an alteration of the local chromatin structure and facilitated activation of distal enhancer elements. The study of human samples of hepatoblastoma showed that DKK1 is strongly upregulated in tumors and associated with poor patient outcome. Taken together our results suggest that the regulation of 3D chromatin architecture by macroH2A histone variants has a central role in the response and regulation of paracrine signalling that might be relevant for the interaction of cancers with immune cells and other cells in their microenvironment.
2022-06-21 | GSE203475 | GEO
Project description:The histone variant macroH2A has been shown to generally associate with transcriptionally silent chromatin states. However, how macroH2A regulates the chromatin structure and functions in transcriptional process still remains elusive at the molecular level. In this study, we demonstrate that the incorporation of macroH2A does not affect the stability and the folding dynamics of nucleosome, but greatly impairs the FACT’s maintenance function at the nucleosome level. FACT can greatly impair the stability of macroH2A nucleosome, and quickly deplete the macroH2A nucleosome after the first unfolding process. Furthermore, we identify the key residue S139 of macroH2A, whose mutation can rescue the FACT’s function to maintain nucleosome integrity. Genome-wide analyses show that S139 mutation in macroH2A reshapes the position of macroH2A and regulates the stimulation-induced transcription in macrophage. Our findings provide mechanistic insights of how histone variant macroH2A coregulates with FACT at the nucleosome level and functions in cell response of macrophage in immunity.
2025-10-01 | GSE248744 | GEO
Project description:The histone variant macroH2A has been shown to generally associate with transcriptionally silent chromatin states. However, how macroH2A regulates the chromatin structure and functions in transcriptional process still remains elusive at the molecular level. In this study, we demonstrate that the incorporation of macroH2A does not affect the stability and the folding dynamics of nucleosome, but greatly impairs the FACT’s maintenance function at the nucleosome level. FACT can greatly impair the stability of macroH2A nucleosome, and quickly deplete the macroH2A nucleosome after the first unfolding process. Furthermore, we identify the key residue S139 of macroH2A, whose mutation can rescue the FACT’s function to maintain nucleosome integrity. Genome-wide analyses show that S139 mutation in macroH2A reshapes the position of macroH2A and regulates the stimulation-induced transcription in macrophage. Our findings provide mechanistic insights of how histone variant macroH2A coregulates with FACT at the nucleosome level and functions in cell response of macrophage in immunity.
2025-05-01 | GSE248551 | GEO
Project description:Here we report that the histone variant macroH2A acts as a barrier to induced pluripotency. Using fibroblasts isolated from macroH2A double knockout mice, we observed enhanced reprogramming efficiency compared to fibroblasts from wild type animals. We further show that macroH2A isoforms act synergistically in this process. Genomic analysis in wild type fibroblasts reveals that macroH2A1 and H3K27me3 domains co-localize and occupy pluripotency genes. While the absence of macroH2A does not affect H3K27me3 in fibroblasts, macroH2A1 is highly enriched at a set of Utx target genes that are reactivated early during iPS reprogramming.
2013-03-01 | GSE40813 | GEO
Project description:Eukaryotic chromatin structure is highly conserved, with the canonical histone proteins revealing only small sequence changes across species. Yet, all vertebrates exhibit three much larger histone H2A variants, macroH2A. A distinctive feature of these atypical histones is the globular macrodomain module, which can bind metabolites and is connected to the histone fold through a flexible linker. MacroH2A variants impact heterochromatin organization, transcription regulation and establish a barrier for cellular reprogramming. However, the mechanisms of how these large H2A variants are incorporated into chromatin and the identity of any chaperones required for histone deposition have remained elusive. Here, we developed a split-GFP-based cellular readout for histone incorporation and conducted a genome-wide mutagenesis screen in haploid human cells to identify proteins that regulate macroH2A dynamics. We identified and validated the histone chaperone ANP32B as a regulator of macroH2A chromatin deposition. ANP32B associates with macroH2A in cells and in vitro binds to histones with low nanomolar affinity. In vitro nucleosome assembly assays show that ANP32B stimulates deposition of macroH2A-H2B and not of H2A-H2B onto tetraso me. In cells, depletion of ANP32B in cells strongly affects global macroH2A deposition, revealing ANP32B as a macroH2A chaperone. Our study highlights the power of haploid cell functional genomics coupled with cellular imaging to identify factors that are required for chromatin plasticity and diversity.
2023-11-07 | GSE241387 | GEO