Similar Datasets
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.
2022-09-20 | GSE161857 | 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 modulates inflammatory response in cancer
| PRJNA679719 | ENA
Project description:The histone variant macroH2A modulates inflammatory response in cancer [HepG2]
| PRJNA679723 | ENA
Project description:The histone variant macroH2A modulates inflammatory response in cancer [xenograft]
| PRJNA679724 | ENA
Project description:The histone variant macroH2A modulates inflammatory response in cancer [UMI-4C]
| PRJNA840922 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-10-15 | E-GEOD-57089 | biostudies-arrayexpress
Project description:macroH2A is an H2A variant with a highly unusual structural organization. It has a C-terminal domain connected to the N-terminal histone domain by a linker. Crystallographic and biochemical studies show that changes in the L1 loop in the histone fold region of macroH2A impact the structure and potentially the function of nucleosomes. The 1.6-A X-ray structure of the nonhistone region reveals an alpha/beta fold which has previously been found in a functionally diverse group of proteins. This region associates with histone deacetylases and affects the acetylation status of nucleosomes containing macroH2A. Thus, the unusual domain structure of macroH2A integrates independent functions that are instrumental in establishing a structurally and functionally unique chromatin domain.
| S-EPMC1190287 | biostudies-literature
Project description:How various layers of epigenetic repression restrict somatic cell nuclear reprogramming is poorly understood. The transfer of mammalian somatic cell nuclei into Xenopus oocytes induces transcriptional reprogramming of previously repressed genes. Here, we address the mechanisms that restrict reprogramming following nuclear transfer by assessing the stability of the inactive X chromosome (Xi) in different stages of inactivation. We find that the Xi of mouse post-implantation-derived epiblast stem cells (EpiSCs) can be reversed by nuclear transfer, while the Xi of differentiated or extraembryonic cells is irreversible by nuclear transfer to oocytes. After nuclear transfer, Xist RNA is lost from chromatin of the Xi. Most epigenetic marks such as DNA methylation and Polycomb-deposited H3K27me3 do not explain the differences between reversible and irreversible Xi. Resistance to reprogramming is associated with incorporation of the histone variant macroH2A, which is retained on the Xi of differentiated cells, but absent from the Xi of EpiSCs. Our results uncover the decreased stability of the Xi in EpiSCs, and highlight the importance of combinatorial epigenetic repression involving macroH2A in restricting transcriptional reprogramming by oocytes.
| S-EPMC3116279 | biostudies-literature