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The histone variant macroH2A modulates inflammatory response in cancer [UMI-4C]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203475 | GEO | 2022/06/21

REPOSITORIES: GEO

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The histone variant macroH2A modulates inflammatory response in cancer [xenograft]

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

The histone variant macroH2A modulates inflammatory response in cancer [HepG2]

2022-09-20 | GSE161857 | GEO

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

Mesenchymal stem cell-derived extracellular vesicles

Project description:Therapeutic benefits of mesenchymal stem/stromal cells (MSCs) are now widely believed to come from their paracrine signalling, i.e. secreted factors such as cytokines, chemokines, and extracellular vesicles (EVs). Cell-free therapy using EVs is an active and emerging field in regenerative medicine. The cellular environment of MSCs is of critical importance when directing paracrine activity. Typical 2D cultivation of stem cells on tissue culture plastic is far removed from the physiological environment of MSCs. The application of 3D cell culture allows MSCs to adapt to their cellular niche environment which, in turn, influences their paracrine signalling activity. In this study we evaluated the impact of 3D MSCs culture on EVs secretion and cargo proteome composition and functional assessment. The outcome highlights critical differences between MSC-EVs obtained from different culture microenvironments, which should be considered when scaling up MSC culture for clinical manufacturing.

2021-11-17 | PXD029766 | Pride

Transcription profiling of human cell lines reveals Dickkopf-1 is down-regulated by MYCN and inhibits neuroblastoma cell proliferation

Project description:Neuroblastomas are tumors of the developing peripheral sympathetic nervous system, which originates from the neural crest. Twenty percent of neuroblastomas show amplification of the MYCN oncogene, which correlates with poor prognosis. The MYCN transcription factor can activate and repress gene expression. To broaden our insight in the spectrum of genes down-regulated by MYCN, we generated gene expression profiles of the neuroblastoma cell lines SHEP-21N and SKNAS-NmycER, in which MYCN activity can be regulated. In this study, we show that MYCN suppresses the expression of Dickkopf-1 (DKK1) in both cell lines. DKK1 is a potent inhibitor of the wnt/ï?¢-catenin signalling cascade, which is known to function in neural crest cell migration. We generated a DKK1 inducible cell line, IMR32-DKK1, which showed impaired proliferation upon DKK1 expression. Surprisingly, DKK1 expression did not inhibit the canonical wnt/ï?¢-catenin signalling, suggesting a role of DKK1 in an alternative route of the wnt pathway. Gene expression profiling of two IMR32-DKK1 clones showed that only a few genes, amongst which SYNPO2, were up-regulated by DKK1. SYNPO2 encodes an actin-binding protein and was previously found to inhibit proliferation and invasiveness of prostate cancer cells. These results suggest that MYCN might stimulate cell proliferation by inhibiting the expression of DKK1. DKK1 might exert part of its growth suppressive effect by induction of SYNPO2 expression. Experiment Overall Design: Single time course experiment, including 4 time points

2008-06-16 | E-GEOD-8066 | biostudies-arrayexpress

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 [3D chromatin]

2023-06-09 | GSE229531 | GEO

Dickkopf-1 is down-regulated by MYCN and inhibits neuroblastoma cell proliferation

Project description:Neuroblastomas are tumors of the developing peripheral sympathetic nervous system, which originates from the neural crest. Twenty percent of neuroblastomas show amplification of the MYCN oncogene, which correlates with poor prognosis. The MYCN transcription factor can activate and repress gene expression. To broaden our insight in the spectrum of genes down-regulated by MYCN, we generated gene expression profiles of the neuroblastoma cell lines SHEP-21N and SKNAS-NmycER, in which MYCN activity can be regulated. In this study, we show that MYCN suppresses the expression of Dickkopf-1 (DKK1) in both cell lines. DKK1 is a potent inhibitor of the wnt/beta-catenin signalling cascade, which is known to function in neural crest cell migration. We generated a DKK1 inducible cell line, IMR32-DKK1, which showed impaired proliferation upon DKK1 expression. Surprisingly, DKK1 expression did not inhibit the canonical wnt/beta-catenin signalling, suggesting a role of DKK1 in an alternative route of the wnt pathway. Gene expression profiling of two IMR32-DKK1 clones showed that only a few genes, amongst which SYNPO2, were up-regulated by DKK1. SYNPO2 encodes an actin-binding protein and was previously found to inhibit proliferation and invasiveness of prostate cancer cells. These results suggest that MYCN might stimulate cell proliferation by inhibiting the expression of DKK1. DKK1 might exert part of its growth suppressive effect by induction of SYNPO2 expression. Keywords: DKK1, MYCN, neuroblastoma, Dickkopf

2007-08-24 | GSE8066 | GEO

BV6 induces an early wave of gene expression via NF-κB and AP-1 and a second wave via TNFα/TNFR1 signaling

Project description:Smac mimetics are considered as promising cancer therapeutics, but little is yet known about how they alter gene expression. In this study we used an unbiased genome-wide expression array to investigate Smac mimetic BV6-induced gene regulation in breast cancer cell lines. Kinetic analysis revealed that BV6 alters gene expression in two waves. The first wave primarily involves NF-κB- and AP-1 families of transcription factors, while the second wave largely depends on tumor necrosis factor receptor 1 (TNFR1) signaling. Interestingly, disrupting auto-/paracrine tumor necrosis factor-α (TNFα)/ (TNFR1) signaling by knockdown of TNFR1 strongly attenuates the BV6-induced second wave of gene expression and upregulation of many pathways including NF-κB signaling, apoptosis and immune signalling, but not MAPK signaling pathways. Consistently, BV6 stimulates phosphorylation of cJun, a marker of MAPK cascade activation, irrespective of the presence or absence of the TNFα blocking antibody Enbrel. We show here in a comprehensive overview that BV6-induced gene expression in breast cancer cells takes place in a time- as well as TNFR1-dependent manner.

2018-02-05 | GSE107912 | GEO

The small signalling peptide CEP5 attenuates the dynamic AUX/IAA equilibrium

Project description:Root architecture is vital for plant growth and largely depends on primary root growth and lateral root development. Several plant hormones have been shown to affect root architecture among which auxin has been granted a central role. Lately, small signalling peptides also emerged as potential molecular components regulating root growth and development. Here, we identified C-TERMINALLY ENCODED PEPTIDE 5 (CEP5) as a novel, phloem poleexpressed paracrine signal for lateral root initiation. Our genetic, biochemical and pharmacological results show that CEP5 counteracts auxin signalling by stabilizing AUXIN/INDOLE ACETIC ACID (AUX/IAA) transcriptional repressors, suggesting the existence of an additional control mechanism through which plants can attenuate auxin signalling in a developmental context. Reducing CEP5 expression levels resulted in an increased auxin response and subsequently interfered with the normal progression through lateral root developmental stages.

2022-03-01 | PXD002589 | Pride

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