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RNAseq in protected BAP1 mESc

ABSTRACT: Malignancies arising from mutation of tumor suppressor genes display an unexplained tissue proclivity. For example, tumor suppressor BAP1 encodes a ubiquitously expressed deubiquitinase for histone H2A but germline mutations predominantly cause uveal melanomas and mesotheliomas. We show that BAP1 inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver and pancreas, whereas melanocytes and mesothelial cells remain viable. E3 ligase RNF2, which silences genes by monoubiquitinating H2A, promoted apoptosis in BAP1-deficient cells by suppressing the pro-survival genes Bcl-2 and Mcl-1. Our data argue that BAP1 modulates gene expression by countering H2A ubiquitination, but its loss only promotes tumorigenesis in cells that do not engage an RNF2-dependent apoptotic program. We propose that intolerance of BAP1 loss, and perhaps the loss of other tumor suppressors, restricts the mutant tumor spectrum.

ORGANISM(S): Mus musculus

PROVIDER: GSE120413 | GEO | 2019/03/26

REPOSITORIES: GEO

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RNAseq in BAP1 KO primary mouse melanocytes

Project description:Malignancies arising from mutation of tumor suppressor genes display an unexplained tissue proclivity. For example, tumor suppressor BAP1 encodes a ubiquitously expressed deubiquitinase for histone H2A but germline mutations predominantly cause uveal melanomas and mesotheliomas. We show that BAP1 inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver and pancreas, whereas melanocytes and mesothelial cells remain viable. E3 ligase RNF2, which silences genes by monoubiquitinating H2A, promoted apoptosis in BAP1-deficient cells by suppressing the pro-survival genes Bcl-2 and Mcl-1. Our data argue that BAP1 modulates gene expression by countering H2A ubiquitination, but its loss only promotes tumorigenesis in cells that do not engage an RNF2-dependent apoptotic program. We propose that intolerance of BAP1 loss, and perhaps the loss of other tumor suppressors, restricts the mutant tumor spectrum.

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Rare germline heterozygous missense variants of the BRCA1-Associated Protein 1 gene, BAP1, heterozygous missense variants cause a syndromic neurodevelopmental disorder

Project description:Nuclear deubiquitinase BAP1 (BRCA1-Associated Protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor gene whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a NDD or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic neurodevelopmental disorder (NDD). Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired in matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.

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Mesothelioma tumor aCGH profiles

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2011-05-19 | E-GEOD-29383 | biostudies-arrayexpress

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Proteomic analysis identifies novel BRCA1-associated protein 1 binding proteins

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2012-06-09 | E-GEOD-25540 | biostudies-arrayexpress

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Project description:BAP1 has been studied as a tumor suppressor. Our aim was to characterize genes that were altered in various hematopoietic cell types upon deletion of BAP1. BAP1 WT versus KO cells.

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