Expression data from HCCC-9810 cells with MBD5 or BAP1 knockdown
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE111817 | GEO | 2018/03/15
REPOSITORIES: GEO
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Project description: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.
2022-09-15 | GSE196860 | GEO
Project description:MBD5 and MBD6 stabilize the BAP1 complex and promote BAP1-dependent cancer
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Project description:Expression data from HCCC-9810 cells with MBD5 or BAP1 knockdown
| PRJNA438273 | ENA
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
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
Project description:Background: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. Methods: In an effort to gain insight into the complex interactions associated with genetic alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of the heterozygous hypomorphic Mbd5+/GT mouse model and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. Results: Gene expression analyses of three brain regions from Mbd5+/GT mice showed cortex as the region most affected by the knockdown, indicating context-dependent effects. Gene co-expression network analyses revealed gene clusters that are associated with MBD5 knockdown and enriched for GPCR signaling and terms related to ciliary function. We also identified genes that were downregulated in both models such as EPHA3, OLIG1, related to neuronal development and glial function. Limitations: These analyses were performed in a limited number of brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across brain tissues during early brain developmentneurodevelopment in ASD. Conclusions: Our study points to transcriptional consequences of Mbd5 disruption in the brain and suggests a link between MBD5 and pathways such as ciliary function that are associated with established developmental disorders and syndromes.
2020-01-28 | GSE144277 | GEO
Project description:The deubiquitinase BAP1 is a candidate tumor suppressor regulating cell proliferation in human and is required for development in Drosophila. BAP1 is assembled into high molecular weight transcriptional multi-protein complexes. In order to identify potential BAP1 target genes, global mRNA expression profiling using microarrays was conducted. U2OS cells, transfected with a non-target control shRNA or shRNAs targeting BAP1, were selected with puromycin containing medium and then synchronized at the G1/S border to allow comparative analysis of gene expression.
2010-11-05 | E-GEOD-23035 | biostudies-arrayexpress
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
Project description:BackgroundBRCA1-associated protein 1 (BAP1) is an ubiquitin carboxy-terminal hydrolase, which forms a multi-protein complex with different epigenetic factors, such as ASXL1-3 and FOXK1/2. At the chromatin level, BAP1 catalyzes the removal of mono-ubiquitination on histone H2AK119 in collaboration with other subunits within the complex and functions as a transcriptional activator in mammalian cells. However, the crosstalk between different subunits and how these subunits impact BAP1's function remains unclear.ResultsWe 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 the chromatin. We further identify a novel Drosophila protein, the six-banded (SBA), as an ortholog of human MBD5 and MBD6, and demonstrate that the core modules of the BAP1 complex is structurally and functionally conserved from Drosophila (Calypso/ASX/SBA) to human cells (BAP1/ASXL/MBD). Dysfunction of the BAP1 complex induced by the misregulation/mutations in its subunit(s) are frequent in many human cancers. In BAP1-dependent human cancers, such as small cell lung cancer (SCLC), MBD6 tends to be a part of the predominant complex formed. Therefore, depletion of MBD6 leads to a global loss of BAP1 occupancy at the chromatin, resulting in a reduction of BAP1-dependent gene expression and tumor growth in vitro and in vivo.ConclusionsWe characterize MBD5 and MBD6 as important regulators of the BAP1 complex and maintain its transcriptional landscape, shedding light on the therapeutic potential of targeting MBD5 and MBD6 in BAP1-dependent human cancers.
| S-EPMC9523997 | biostudies-literature
Project description:Background: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. Methods: In an effort to gain insight into the complex interactions associated with genetic alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of the heterozygous hypomorphic Mbd5+/GT mouse model and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. Results: Gene expression analyses of three brain regions from Mbd5+/GT mice showed cortex as the region most affected by the knockdown, indicating context-dependent effects. Gene co-expression network analyses revealed gene clusters that are associated with MBD5 knockdown and enriched for GPCR signaling and terms related to ciliary function. We also identified genes that were downregulated in both models such as EPHA3, OLIG1, related to neuronal development and glial function. Limitations: These analyses were performed in a limited number of brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across brain tissues during early brain developmentneurodevelopment in ASD. Conclusions: Our study points to transcriptional consequences of Mbd5 disruption in the brain and suggests a link between MBD5 and pathways such as ciliary function that are associated with established developmental disorders and syndromes.
2020-01-28 | GSE144279 | GEO