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MacroH2A restricts melanoma progression via inhibition of chemokine expression in cancer-associated fibroblasts [3D chromatin]

ABSTRACT: MacroH2A has tumor suppressive functions in melanoma and other cancers, yet its role in the tumor microenvironment remains unappreciated. Using an autochthonous, immunocompetent mouse model of melanoma, we demonstrate that mice devoid of macroH2A variants exhibit increased tumor burden compared to wild type counterparts. MacroH2A-deficient tumors accumulate immunosuppressive monocytes and decreased functional cytotoxic T cells, and consistent with this compromised anti-tumor response, exhibit upregulation of pro-inflammatory cytokines. Single cell transcriptomics not only identifies cancer-associated fibroblasts (CAFs), whose frequency and activation increase in the absence of macroH2A, as the source of myeloid chemoattractants but also demonstrates dedifferentiation along the neural crest lineage of the tumor compartment. CAFs lacking macroH2A display hyper-inducible inflammatory gene expression and promoters of these genes present increased chromatin looping to enhancers that gain H3K27ac. In sum, we reveal a tumor suppressive role for macroH2A variants through regulation of chromatin architecture of inflammatory genes in the tumor stroma with potential implications for human melanoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE229531 | GEO | 2023/06/09

REPOSITORIES: GEO

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MacroH2A restricts melanoma progression via inhibition of chemokine expression in cancer-associated fibroblasts [spatial transcriptomics]

Project description:MacroH2A has tumor suppressive functions in melanoma and other cancers, yet its role in the tumor microenvironment remains unappreciated. Using an autochthonous, immunocompetent mouse model of melanoma, we demonstrate that mice devoid of macroH2A variants exhibit increased tumor burden compared to wild type counterparts. MacroH2A-deficient tumors accumulate immunosuppressive monocytes and decreased functional cytotoxic T cells, and consistent with this compromised anti-tumor response, exhibit upregulation of pro-inflammatory cytokines. Single cell transcriptomics not only identifies cancer-associated fibroblasts (CAFs), whose frequency and activation increase in the absence of macroH2A, as the source of myeloid chemoattractants but also demonstrates dedifferentiation along the neural crest lineage of the tumor compartment. CAFs lacking macroH2A display hyper-inducible inflammatory gene expression and promoters of these genes present increased chromatin looping to enhancers that gain H3K27ac. In sum, we reveal a tumor suppressive role for macroH2A variants through regulation of chromatin architecture of inflammatory genes in the tumor stroma with potential implications for human melanoma.

2023-06-09 | GSE229532 | GEO

MacroH2A restricts melanoma progression via inhibition of chemokine expression in cancer-associated fibroblasts [epigenomics]

Project description:The histone variant macroH2A has been implicated as a tumor suppressor in melanoma and other cancers, yet its role in the tumor microenvironment remains unappreciated. Here we show that mice constitutively lacking macroH2A variants exhibit increased melanoma tumor burden compared to their wild-type counterparts, which is associated with an altered intratumoral immune cell compartment. MacroH2A-deficient tumors display an accumulation of immunosuppressive monocytes and decreased functional cytotoxic T cells. Consistent with this compromised anti-tumor response, macroH2A-deficient tumors displayed upregulation of chemokines such as Ccl2, Cxcl1 and Il6. Through single cell transcriptomics of the entire melanoma microenvironment, we identified the source of these pro-tumor myeloid chemoattractants as cancer-associated fibroblasts, whose frequency and activation were increased in the absence of macroH2A. Chemokine gene expression was hyper-inducible in the absence of macroH2A and accompanied by an altered epigenetic landscape. In sum, we uncovered a tumor suppressive role for macroH2A through repression of chemokine induction in the tumor stroma.

2023-06-09 | GSE200734 | GEO

MacroH2A restricts melanoma progression via inhibition of chemokine expression in cancer-associated fibroblasts [scRNA-seq]

2023-06-09 | GSE229530 | GEO

MacroH2A restricts melanoma progression via inhibition of chemokine expression in cancer-associated fibroblasts [RNA-seq]

2023-06-09 | GSE200725 | GEO

Purification of macroH2A.1 and macroH2A.2 Nucleosomes from Fetal Mouse Liver

Project description:MacroH2As core histone variants have a unique structure that includes C-terminal nonhistone domain. MacroH2As are highly conserved in vertebrates, and are thought to regulate gene expression. However the nature of genes regulated by macroH2As and the biological significance of macroH2As for the organism remain unclear. Our gene expression studies indicate that macroH2A.1 and macroH2A.2 work together to regulate specific genes. In these studies we examine the distributions of macroH2A.1 and macroH2A.2 nucleosomes to determine if they are localized to the genes that show altered expression in macroH2A knockout mouse liver. MacroH2A.1 and macroH2A.2 nucleosomes prepared from ~ 50 fetal mouse livers were purified by thio-affinity chromatography. Five samples were sequenced: Thiopropyl Sepharose, Normal Liver - contains mononucleosomal DNA from macroH2A.1-containing nucleosomes; Activate Thiol Sepharose, Normal Liver - contains mononucleosomal DNA primarily from macroH2A.2-containing nucleosomes. Starting Material, Normal Liver - this is a reference samplefor the first two samples. It contains mononucleosomal DNA from bulk fetal liver chromatin. Activated Thiol Sepharose, Knockout Livers - this is a control sample that contains mononucleosomal DNA from non-macroH2A nucleosomes that contaminate the macroH2A.2 nucleosomes. This fraction was prepared from macroH2A1/2 double knockout fetal livers; Starting Material, Knockout Liver - this is a reference sample for the fourth sample. It contains mononucleosomal DNA from bulk chromatin prepared from macroH2A1/2 double knockout fetal livers.

2014-10-15 | E-GEOD-57796 | biostudies-arrayexpress

Purification of macroH2A.1 and macroH2A.2 Nucleosomes from Fetal Mouse Liver

2014-10-15 | GSE57796 | GEO

Expression data from macroH2A shRNA lines

Project description:Cancer is a disease of both genetic and epigenetic changes. While increasing evidence demonstrates that oncogenic progression entails chromatin-mediated changes such as DNA methylation, the role of histone variants in cancer initiation and progression currently remains unexplored. Here, we report that the histone variant macroH2A (mH2A) suppresses tumour progression of malignant melanoma. We hypothesized that loss of mH2A could contribute to melanoma progression by relieving repression of cell cycle- and metastasis-related genes. To gain insight into the transcriptional state of mH2A1 and mH2A2-deficient cells, we examined their gene expression profiles using Affymetrix microarrays. Murine B16-F1 cells with lentiviral shRNAs against mH2A1 and mH2A2 were generated along with control shRNA (against GFP) and used for the microarray analysis. Two independent biological replicates were used.

2010-12-23 | E-GEOD-19181 | biostudies-arrayexpress

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

Project description:Genetic loss-of-function studies in development, cancer and somatic cell reprogramming have suggested that the group of macroH2A histone variants might function through stabilizing the differentiated state by a yet unknown mechanism. Here, we present results demonstrating that macroH2A variants have a major function in maintaining nuclear organization and heterochromatin architecture. Specifically, we find that a substantial amount of macroH2A is associated with heterochromatic repeat sequences. We further identify macroH2A on sites of interstitial heterochromatin decorated by H3K9me3. Loss of macroH2A leads to major defects in nuclear organization including reduced nuclear circularity, disruption of nucleoli and a global loss of dense heterochromatin. Domains formed by repeat sequences when depleted of macroH2A are disorganized, expanded and fragmented and mildly re-expressed. On the molecular level we find that macroH2A is required for the interaction of repeat sequences with the nucleostructural protein Lamin B1. Taken together our results argue that a major function of macroH2A histone variants is to link nucleosome composition to higher order chromatin architecture.

2017-03-21 | GSE58175 | GEO

The histone chaperone ANP32B regulates chromatin incorporation of the atypical human histone variant macroH2A

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

Expression data from macroH2A shRNA lines

2010-12-23 | GSE19181 | GEO

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