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Genome-wide H3K27me3 profile in in vitro produced bovine morula treated with MAT2A inhibitor

ABSTRACT: We obtained genome-wide profiles of histone H3 lysine 27 trimethylation (H3K27me3) in bovine morula which had been in vitro treated with a methionine adenosyltransferase 2A (MAT2A) inhibitor from the 8-16 cell stage. Sequencing center: NODAI Genome Research Center, Tokyo University of Agriculture

ORGANISM(S): Bos taurus

PROVIDER: GSE198293 | GEO | 2022/05/31

REPOSITORIES: GEO

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Transcriptomic profile in in vitro produced bovine morulae treated with MAT2A inhibitor

Project description:We obtained transcriptomic profiles in bovine morulae which had been in vitro treated with a methionine adenosyltransferase 2A (MAT2A) inhibitor from the 8-16 cell stage.

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Epigenome-wide impact of MAT2A sustains the androgen-indifferent state and confers synthetic vulnerability in ERG fusion-positive prostate cancer

Project description:Castration-resistant prostate cancer (CRPC) is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. Here, we identify a novel role of methionine adenosyltransferase 2a (MAT2A) as a driver of the androgen-indifferent state in ERG fusion-positive CRPC. We show that MAT2A is upregulated in CRPC and cooperates with ERG in promoting cell plasticity, stemness and tumorigenesis. RNA, ATAC and ChIP sequencing coupled with mass spectrometry analysis of histone post-translational modifications show that MAT2A broadly impacts the transcriptional and epigenetic landscape. MAT2A enhances H3K4me2 at multiple genomic sites promoting the expression of pro-tumorigenic non-canonical AR target genes in CRPC models. Genetic and pharmacological inhibition of MAT2A in preclinical models reversed this transcriptional and epigenetic remodeling, promoting luminal differentiation and improving the response to AR and EZH2 inhibitors. This data reveals a previously unrecognized function of MAT2A in epigenetic reprogramming and a synthetic vulnerability to MAT2A inhibitors in ERG fusion-positive CRPC.

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MAT2A and methionine dependency are indispensible for H3K27M mutant gliomas.

Project description:Gliomas bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors. H3K27M mutant tumors display unique epigenomes with global loss of the chromatin repressive H3K27 trimethylation mark. Here, we generated a syngeneic H3K27M mouse model to study the dependence upon amino acid (AA) metabolism by performing an AA drop out screen. H3K27M mutant cells, but not histone wildtype cells, were highly dependent on the amino acid, methionine. Interrogating the methionine cycle dependency through an siRNA screen identified the enzyme Methionine Adenosyltransferase 2A (MAT2A), which catalyzes production of S-adenosylmethionine (SAM), a methyl donor. Sensitivity to MAT2A loss in H3K27M mutant cells was not mediated through the canonical mechanism of MTAP deletion; instead, H3K27M mutant cells have lower MAT2A protein levels, which is mediated by Adenosylmethionine Decarboxylase 1 (AMD1) production of decarboxylated SAM (dcSAM). MAT2A loss induces global depletion of H3K36me3, a potent chromatin mark of transcriptional elongation, as evaluated by quantitative chromatin immunoprecipitation with reference exogenous genome sequencing (ChIP-Rx-Seq) in multiple DIPG lines. Tandem H3K36me3 ChIP-Rx-seq and RNA-seq identified several oncogenic and developmental transcriptional programs associated with MAT2A loss. Moreover, inducible knockdown of MAT2A or methionine-restricted diets (MR) extended survival in both syngeneic and patient-derived xenograft models (PDXs) in vivo. Collectively, our results provide novel connections between AA metabolism and the epigenome in H3K27M gliomas, suggesting that MAT2A, a central regulator of methionine metabolism, presents exploitable therapeutic vulnerabilities in H3K27M gliomas.

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Genome-wide H3K27me3 profile in in vitro produced bovine morula treated with MAT2A inhibitor

Project description:Genome-wide H3K27me3 profile in in vitro produced bovine morula treated with MAT2A inhibitor

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TGF-β1/p65/MAT2A: a novel pathway involved in the regulation of intracellular SAM and liver fibrogenesis - Part2

2019-11-12 | PXD011135 | Pride

Genome-wide mapping of MAT2A-associsted regions in bovine blastocysts

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