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Systematic functional characterization of BAF mutations yields novel intra-complex synthetic lethalities [ChIP-Seq]

ABSTRACT: Aberrations in genes coding for subunits of the BAF chromatin remodeling complex are highly abundant in human cancers. Currently, it is not understood how these loss-of-function mutations contribute to cancer development and how they can be targeted therapeutically. The cancer type specific occurrence patterns of certain subunit mutations suggest subunit-specific effects on BAF complex function, possibly by the formation of aberrant residual complexes. Here, we systematically characterize the effects of individual subunit loss on complex composition, chromatin accessibility and gene expression in a panel of knock-out cell lines deficient for 22 targetable BAF subunits. We observe strong, specific and often discordant alterations dependent on the targeted subunit and show that these explain intra-complex co-dependencies, including the novel synthetic lethal interactions SMARCA4-ARID2, SMARCA4-ACTB and SMARCC1-SMARCC2. These data provide insights into the role of different BAF subcomplexes in genome-wide chromatin organization and suggest novel approaches to therapeutically target BAF mutant cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108387 | GEO | 2019/04/30

REPOSITORIES: GEO

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Systematic characterization of BAF mutations explains intra-complex synthetic lethalities

Project description:Aberrations in genes coding for subunits of the BAF chromatin remodeling complex are highly abundant in human cancers. Currently, it is not understood how these loss-of-function mutations contribute to cancer development and how they can be targeted therapeutically. The cancer type specific occurrence patterns of certain subunit mutations suggest subunit-specific effects on BAF complex function, possibly by the formation of aberrant residual complexes. Here, we systematically characterize the effects of individual subunit loss on complex composition, chromatin accessibility and gene expression in a panel of knock-out cell lines deficient for 22 targetable BAF subunits. We observe strong, specific and often discordant alterations dependent on the targeted subunit and show that these explain intra-complex co-dependencies, including the novel synthetic lethal interactions SMARCA4-ARID2, SMARCA4-ACTB and SMARCC1-SMARCC2. These data provide insights into the role of different BAF subcomplexes in genome-wide chromatin organization and suggest novel approaches to therapeutically target BAF mutant cancers.

2019-08-01 | PXD013102 | Pride

Systematic functional characterization of BAF mutations yields novel intra-complex synthetic lethalities [RNA-Seq]

2019-04-30 | GSE108388 | GEO

Systematic functional characterization of BAF mutations yields novel intra-complex synthetic lethalities [ATAC-Seq]

2019-04-30 | GSE108386 | GEO

Acute BAF perturbation causes immediate changes in chromatin accessibility

Project description:Loss-of-function mutations in genes coding for subunits of the large, multifarious BRG1/BRM associated factor (BAF) chromatin remodeling complexes are frequently causative for cancer or developmental diseases1-5. Cells lacking the most frequently mutated subunits like the ATPase SMARCA4 typically exhibit drastic chromatin accessibility changes, especially of important regulatory regions6-12. However, so far it remains unknown how these changes are established over time, and whether they are causative for intra-complex synthetic lethalities abrogating the formation (SMARCC1-SMARCC2)8,13,14 or activity (SMARCA4-SMARCA2)15-17 of BAF complexes. Here, we utilize the dTAG system18 to induce acute degradation of BAF subunits in wild-type and BAF mutant backgrounds and analyze the resulting chromatin accessibility changes with high kinetic resolution. We observe that chromatin alterations are established faster than the duration of one cell cycle and that maintaining genome accessibility requires constant ATP-dependent remodeling. Completely abolishing BAF complex function by acute degradation of a synthetic lethal subunit in a paralog-deficient background results in a near-complete loss of chromatin accessibility at BAF-controlled sites, especially at super-enhancers, providing a mechanism for intra-complex synthetic lethalities.

2020-12-23 | PXD018381 | Pride

A structural model of the human mSWI/SNF (BAF) complex bound to the nucleosome informs disease mechanisms

Project description:Mammalian SWI/SNF complexes are multi-component ATP-dependent chromatin-remodeling complexes that regulate genomic architecture. Here we present the first structural model of the human canonical BAF chromatin-remodeling complex bound to a nucleosome generated using cryo-EM, cross-linking mass spectrometry, and homology modeling. Endogenously-purified BAF tethers to the nucleosome H2A/H2B acidic patch regions bilaterally through the SMARCB1 C-terminal helix and a SMARCA4 C-terminal post-SnAc region, each of which are mutated in disease and disrupt nucleosome remodeling. We describe the structural organization of the BAF core module, a connecting ARP module and the ATPase module, scaffolded by the SMARCA4/2 ATPase subunits. Importantly, we assign and model disease-associated mutations throughout the entire BAF complex, identifying mutations that break identified subunit–nucleosome contacts and subunit–subunit interfaces of BAF in the nucleosome-bound conformation. Taken together, this comprehensive structural model of the human BAF complex provides the first insights into the functional impact of mutations that cause cancer and other diseases.

2021-02-10 | PXD020992 | Pride

Dynamic BAF chromatin remodeling complex subunit inclusion promotes temporally distinct gene expression programs in cardiogenesis

Project description:Chromatin remodeling complexes instruct cellular differentiation and lineage specific transcription. The BRG1/BRM associated factor (BAF) complexes are important for several aspects of differentiation. We show that the catalytic subunit Brg1 has a specific role in cardiac precursors (CPs) to initiate cardiac gene expression programs and repress non-cardiac expression. Using immunoprecipitation immunopurification with mass spectrometry we determined the dynamic composition of BAF complexes during mammalian cardiac differentiation, identifying several cell-type specific subunits. We focused on the CP- and cardiomyocytes (CM)-enriched subunits BAF60c (SMARCD3) and BAF170 (SMARCC2). Baf60c and Baf170 co-regulate gene expression with Brg1 in CPs, and in CMs their loss results in broadly deregulated cardiac gene expression. BRG1, BAF60, and BAF170 modulate chromatin accessibility, to either promote accessibility at activated genes, while closing up chromatin at repressed genes. BAF60c and BAF170 are required for proper BAF complex composition, and BAF170 loss leads to retention of BRG1 at CP-specific enhancers. Thus, dynamic interdependent BAF complex subunit assembly modulates chromatin states and thereby participates in directing temporal gene expression programs in cardiogenesis.

2019-11-13 | PXD012721 | Pride

Acute BAF perturbation causes immediate changes in chromatin accessibility

Project description:Loss-of-function mutations in genes coding for subunits of the large, multifarious BRG1/BRM associated factor (BAF) chromatin remodeling complexes are frequently causative for cancer or developmental diseases. Cells lacking the most frequently mutated subunits, like the ATPase SMARCA4, typically exhibit drastic chromatin accessibility changes, especially of important regulatory regions. However, so far it remains unknown how these changes are established over time, and whether they are causative for intra-complex synthetic lethalities abrogating the formation or activity of BAF complexes. Here, we utilize the dTAG system to induce acute degradation of BAF subunits in wildtype and BAF mutant backgrounds and analyze the resulting chromatin accessibility changes with high kinetic resolution. We observe that chromatin alterations are established faster than the duration of one cell cycle and that maintaining genome accessibility requires constant ATP-dependent remodeling. Completely abolishing BAF complex function by acute degradation of a synthetic lethal subunit in a paralog-deficient background results in a near-complete loss of chromatin accessibility at BAF-controlled sites, especially at super-enhancers, providing a mechanism for intra-complex synthetic lethalities.

2020-12-22 | GSE148175 | GEO

mSWI/SNF (BAF) Complexes Facilitate Decatentation of DNA by Topoisomerase IIa

Project description:Recent exon sequencing studies of human tumors have revealed that subunits of mSWI/SNF or BAF complexes are mutated in more than 20% of human malignancies, yet the mechanisms involved in tumor suppression is unclear. BAF chromatin remodeling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure and the placement of Polycomb (PcG) across the genome. Several proteins dedicated to this large multi-subunit complex, including SMARCA4 (BRG1) and BAF250A (ARID1A), are mutated at frequencies similar to that of many recognized tumor suppressors. In particular, the core ATPase BRG1 is mutated in 5-10% of childhood medulloblastoma (MB) and greater than 15% of Burkitt's Lymphoma (BL). Here we find a novel function of BAF complexes in decatenating newly replicated sister chromatids, which is necessary for proper chromosome segregation during mitosis. We find that deletion of Brg1, as well as the expression of Brg1 point mutants identified in human tumors leads to anaphase bridge formation (sister chromatids linked by catenated strands of DNA), and a G2/M phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes directly interact with endogenous TopoIIα through BAF250a and are required for TopoIIα binding to about 12,000 sites over the genome. Our results indicate that TopoIIα’s chromatin binding is dependent on the ATPase activity of Brg1, which is compromised in oncogenic Brg1 mutants. These studies indicate that the ability of TopoIIα to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of BAF subunits as tumor suppressors. Examination of sites of TopoIIa activity in WT and Brg1-/- ES cells as defined by TopoIIa-DNA covalent adducts formed in the presence of etoposide

2013-03-30 | E-GEOD-45625 | biostudies-arrayexpress

Single-minded homolog 2 resides in the chromatin protein network of androgen receptor and modulates gene expression in prostate cancer cells Single-minded homolog 2 resides in the chromatin protein network of androgen receptor and modulates gene expression in prostate cancer cells

Project description:We investigated the composition of chromatin protein network around endogenous androgen receptor (AR) in VCaP castration resistant prostate cancer cells using recently developed chromatin-directed proteomic approach called ChIP-SICAP . The androgen-induced AR chromatin protein network contained expected TFs, e.g. HOXB13, chromatin remodeling proteins, e.g. SMARCA4, and several novel candidates not previously associated with AR, e.g. prostate cancer biomarker SIM2. Based on these findings, the role of SMARCA4 and SIM2 was further characterized at AR chromatin domains . Silencing of SIM2 altered chromatin accessibility at a similar number of AR-binding sites as SMARCA4, an established ATPase subunit of the BAF chromatin remodeling complex, often aberrantly expressed in prostate cancer. Despite the wide co-occurrence on chromatin of SMARCA4 and AR, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, in particular those involved in cell morphogenetic changes in epithelial-mesenchymal transition. Silencing of SIM2, in turn, affected the expression of a much larger group of androgen-regulated genes, e.g. those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of VCaP cells and tumor size in chick embryo chorioallantoic membrane assay, further suggesting the importance of SIM2 in the regulation prostate cancer cells.

2021-06-17 | PXD025193 | Pride

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders

Project description:The BAF complex modulates chromatin accessibility. Specific BAF configurations have functional consequences, and subunit switches are essential for cell differentiation. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we reprogrammed ARID1B+/- Coffin-Siris patient-derived skin fibroblasts into iPSCs, and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF), including SMARCA4, and nine additional subunits. ARID1B-BAF acts as a gate-keeper, ensuring exit from pluripotency and lineage commitment, by attenuating NANOG, SOX2 and the thousands of enhancers directly regulated by these two pluripotency factors at the iPSC stage. In iPSCs, these enhancers are maintained active by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks, and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout all stages of CNCC formation. This leads to a persistent and aberrant SOX2 and NANOG activity, which impairs CNCC formation. In fact, despite showing the typical neural crest signature (TFAP2A+, SOX9+), the ARID1B-haploinsufficient CNCCs are also NANOG-positive, in stark contrast with the ARID1B-wt CNCCs, which are NANOG-negative. These findings suggest a connection between ARID1B mutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.

2021-10-12 | PXD028557 | Pride

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