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MBD5 and MBD6 stabilize the BAP1 complex and promote BAP1-dependent cancer

ABSTRACT: The BRCA1-associated protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase (UCH), which forms a multi-protein complex with different epigenetic factors such as ASXL1-3, and FOXK1/2. At chromatin, BAP1 catalyzes the removal of mono-ubiquitination on histone H2AK119 in collaboration with other subunits within the complex, and therefore functions as a transcriptional activator. However, the crosstalk between different subunits and how these subunits impact BAP1 function remains unclear. Here, we report the identification of the methyl-CpG-binding domain proteins 5 and 6 (MBD5 and MBD6) that bind to the C-terminal PHD fingers of the large scaffold subunits ASXL1-3 and stabilize the BAP1 complex at chromatin. We further identified a previously uncharacterized Drosophila protein, the six-banded (SBA), as the ortholog of human MBD5/6. We demonstrated the core module of the BAP1 complex is structurally and functionally conserved during the evolution from Drosophila (Calypso/ASX/SBA) to human cells (BAP1/ASXL/MBD). Dysfunction of the BAP1 complex induced by the misregulation/mutations in each subunit is frequent in human cancer. In BAP1-dependent human cancers, MBD6 tends to be a dominant form. Depletion of MBD6 leads to a global loss of BAP1 occupancy at chromatin, resulting in a reduction of BAP1-dependent gene expression and tumor growth in vitro and in vivo. In summary, our study has uncovered MBD5/6 as important regulators of the BAP1 complex and transcription, and sheds light on the therapeutic potential of targeting MBD5/6 in human cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196860 | GEO | 2022/09/15

REPOSITORIES: GEO

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Epigenetic targeted therapy of leukemia through a hyper-activated BAP1-ASXL1-mutant axis

Project description:The ASXL1 gene is the human homolog of the Drosophila Asx gene, a core subunit in the BAP1 histone H2A deubiquitinase complex. Mutations of ASXL1 occur in multiple myeloid neoplasms and are uniformly associated with poor prognosis. However, the molecular mechanism through which ASXL1 mutations alter BAP1 activity to drive leukemogenesis remains unclear. Here we demonstrate that cancer-associated frame-shift ASXL1 mutations, which were originally proposed to act as destabilizing loss-of-function mutations, in fact encode truncated stable gain-of-function proteins. Truncated ASXL1 protein stabilizes BAP1, enhances BAP1 complex recruitment to chromatin and promotes the expression of numerous leukemia associated genes. Chemical inhibition of BAP1 rescues these changes in gene expression in leukemic cells and inhibits tumor progression. This study represents a breakthrough advance in our understanding of the molecular mechanisms of ASXL1 mutations in leukemic pathogenesis and identifies small molecular inhibitors of BAP1 function as a potential targeted therapy for leukemia.

2021-03-07 | GSE166305 | GEO

BAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation

Project description:In Drosophila, a complex consisting of Calypso and ASX catalyzes H2A deubiquitination and has been reported to act as part of the Polycomb machinery in transcriptional silencing. The mammalian homologs of these proteins (BAP1 and ASXL1/2/3, respectively), are frequently mutated in various cancer types, yet their precise functions remain unclear. Using an integrative approach based on isogenic cell lines generated with CRISPR/Cas9, we uncover an unanticipated role for BAP1 in gene activation. This function requires the assembly of an enzymatically active BAP1-associated core complex (BAP1.com) containing one of the redundant ASXL proteins. We investigate the mechanism underlying BAP1.com-mediated transcriptional regulation and show that it does not participate in Polycomb-mediated silencing. Instead, our results establish that the function of BAP1.com is to safeguard transcriptionally active genes against silencing by the Polycomb Repressive Complex 1.

2019-01-28 | PXD011808 | Pride

Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex

Project description:ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring-Opitz syndrome. Here, we demonstrate that truncated ASXL1 proteins confer enhanced activity on the ASXL1-BAP1 complex. Stable expression of truncated, hyperactive ASXL1-BAP1 complexes in a hematopoietic precursor cell line resulted in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters bore both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes required the catalytic activity of BAP1, indicating these events were downstream consequences of H2AK119Ub erasure. In bone marrow precursors, truncated ASXL1-BAP1 expression cooperated with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo. We propose that pathological ASXL1 mutations confer gain-of-function on the ASXL-BAP1 complex. ChIP-Seq for H2AK119Ub, H3K4me3, H3K27me3 on EML cells. RNA-Seq on EML cells expressing ASXL1(1-479)+BAP1 and control.

2015-03-11 | E-GEOD-65555 | biostudies-arrayexpress

Genome wide binding sites of BAP1, HCF1 and OGT

Project description:We report the genome wide binding sites of BAP1, HCF1 and OGT in bone marrow derived macrophages. De-ubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. Somatic BAP1 mutations occur in various malignancies. We show that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (MDS). Knockin mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with host cell factor–1 (HCF-1), O-linked N-acetylglucosamine transferase (OGT), and the polycomb group proteins ASXL1 and ASXL2 in vivo. OGT and HCF-1 levels were decreased by Bap1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML) so an ASXL/BAP1 complex may suppress CMML. A BAP1 catalytic mutation found in a MDS patient implies that BAP1 loss of function has similar consequences in mice and humans. For BAP1, bone marrow derived macrophages were used differentiated from bone marrow cells of BAP1-3X Flag Tagged KI mice we generated. For OGT and HCF1, bone marrow derived macrophages were used from BAP1 WT mice.

2012-11-07 | E-GEOD-40723 | biostudies-arrayexpress

Bap1 loss results in EZH2 dependent transformation

Project description:BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated Ezh2 expression, and enhanced repression of Polycomb Repressive Complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone.

2015-10-05 | GSE61360 | GEO

Expression data from HCCC-9810 cells with MBD5 or BAP1 knockdown

Project description:MBD5 can physically interact with BAP1. Some genes may be regulated by both MBD5 and BAP1. We used microarrays to check whether the overlaps of differentially expressed genes when knockdown MBD5 or BAP1 were more than that would be expected by chance. Thus, we could suggest that BAP1 was required for the regulatory effect of MBD5

2018-03-15 | GSE111817 | GEO

Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex

2015-03-11 | GSE65555 | GEO

ASXL1/2 links MLL4 and BAP1 on enhancers

Project description:Histone H3K4 monomethyltransferases MLL3 and MLL4 contain a set of uncharacterized PHD fingers. By structural and biochemical assays, we found a novel function of the PHD2 and PHD3 (PHD2/3) fingers of MLL3 and MLL4, revealing their direct binding to the conserved MBH (MLL binding helix) region of ASXL1/2, components of the Polycomb repressive PR-DUB complex. In mouse embryonic stem cells, we observed that BAP1, the catalytic subunit of the PR-DUB complex, physically interacts with MLL4 in an ASXL1/2 MBH-dependent manner. Genomic studies demonstrate that the ASXL1/2 MBH is required for BAP1 binding on active enhancers and suggest that MLL4 facilitates BAP1 binding on active enhancers through ASXL1/2 MBH.

2024-04-30 | GSE248027 | GEO

Genome wide binding sites of BAP1, HCF1 and OGT

2012-11-07 | GSE40723 | GEO

ACD15, ACD21 and SLN regulate accumulation and mobility of MBD6 to silence genes and transposable elements [RNA-seq]

Project description:DNA methylation mediates silencing of transposable elements and genes in part via recruitment of the Arabidopsis MBD5/6 complex, which contains the methyl-CpG-binding domain (MBD) proteins MBD5 and MBD6, and the J-domain containing protein SILENZIO (SLN). Here we characterize two additional complex members: α-crystalline domain containing proteins ACD15 and ACD21. We show that they are necessary for gene silencing, bridge SLN to the complex, and promote higher order multimerization of MBD5/6 complexes within heterochromatin. These complexes are also highly dynamic, with the mobility of complex components regulated by the activity of SLN. Using a dCas9 system, we demonstrate that tethering the ACDs to an ectopic site outside of heterochromatin can drive massive accumulation of MBD5/6 complexes into large nuclear bodies. These results demonstrate that ACD15 and ACD21 are critical components of gene silencing complexes that act to drive the formation of higher order, dynamic assemblies.

2023-09-14 | GSE234530 | GEO

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