Localized condensation of the cBAF remodeler is governed by ARID1A/B and is required for transcriptional activation [CUT&RUN]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE235698 | GEO | 2023/10/01
REPOSITORIES: GEO
Similar Datasets
Project description:This study investigates the role of the ARID1A/B subunits of the cBAF complex using in vitro and cell-based models. Specifically, we find that the N-terminal disordered region of ARID1A/B and the DNA binding ARID domain are required for condensation and proper orientation on chromatin respectively.
2023-10-01 | GSE209959 | GEO
Project description:This study investigates the role of the ARID1A/B subunits of the cBAF complex using in vitro and cell-based models. Specifically, we find that the N-terminal disordered region of ARID1A/B and the DNA binding ARID domain are required for condensation and proper orientation on chromatin respectively.
2023-10-01 | GSE209955 | GEO
Project description:This study investigates the role of the ARID1A/B subunits of the cBAF complex using in vitro and cell-based models. Specifically, we find that the N-terminal disordered region of ARID1A/B and the DNA binding ARID domain are required for condensation and proper orientation on chromatin respectively.
2023-10-01 | GSE209953 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-10-01 | GSE209961 | GEO
Project description:During development, cells make switch-like decisions to activate new gene programs specifying cell lineage. The mechanisms underlying these decisive choices remain unclear. Here we show that the cardiovascular transcriptional coactivator, Myocardin (MYOCD), activates cell identity genes by concentration-dependent and switch-like formation of transcriptional condensates. MYOCD forms such condensates and activates cell identity genes at critical concentration thresholds achieved during smooth muscle cell and cardiomyocyte differentiation. The C-terminal disordered region of MYOCD is necessary and sufficient for condensate formation. Disrupting this region’s ability to form condensates disrupts gene activation. Rescuing condensate formation by replacing this region with disordered regions from functionally unrelated proteins rescues gene activation. Our findings demonstrate that MYOCD condensate formation is required for gene activation during differentiation. We propose that the formation of transcriptional condensates at critical concentrations of cell type-specific regulators provides a molecular switch underlying the activation of key cell identity genes during cell lineage specification.
2024-02-08 | GSE250206 | GEO
Project description:During development, cells make switch-like decisions to activate the expression of new gene programs leading to lineage specification1. The mechanisms underlying these decisive choices remain unclear2. Here we find that Myocardin (MYOCD), a cardiomyocyte and smooth muscle cell-specific transcriptional coactivator3-6, activates lineage-specific gene programs by concentration-dependent and switch-like formation of nuclear condensates. While compartmentalization of the transcriptional machinery by condensates has been associated with gene activation7,8, directly linking the two processes has been a major challenge for the field9,10. By modeling the natural changes in MYOCD concentration during development, coupled with quantitative fluorescence microscopy, single-cell resolution reporter assays, and cellular differentiation assays, we demonstrate that condensate formation is directly linked to transcriptional activation and lineage specification. During cardiomyocyte and smooth muscle cell differentiation, the formation of MYOCD condensates precedes activation of cell identity genes and these condensates are present at sites of cell identity gene transcription. MYOCD condensates form, activate gene expression, and specify cell state at critical concentration thresholds, dependent upon the C-terminal disordered region of MYOCD. Disrupting condensate formation by manipulating the sequence of this region impairs gene activation which can be rescued by replacing this region with condensate-forming disordered regions from functionally unrelated proteins. These results demonstrate that coactivator condensation at critical concentrations enables switch-like changes in gene expression programs crucial for lineage specification.
2024-03-20 | GSE235928 | GEO
Project description:ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancer. Deficiency in its homolog ARID1B is synthetically lethal with ARID1A mutation. However, the functional relationship between these homologs has not been explored. Here we use ATAC-seq, genome-wide histone modification mapping, and expression analysis to examine colorectal cancer cells lacking one or both ARID proteins. We find that ARID1A has a dominant role in maintaining chromatin accessibility at enhancers, while the contribution of ARID1B is evident only in the context of ARID1A mutation. Changes in accessibility are predictive of changes in expression and correlate with loss of H3K4me and H3K27ac marks, nucleosome spacing, and transcription factor binding, particularly at growth pathway genes including MET. We find that ARID1B knockdown in ARID1A mutant ovarian cancer cells causes similar loss of enhancer architecture, suggesting that this is a conserved function underlying the synthetic lethality between ARID1A and ARID1B.
2017-09-29 | GSE101974 | GEO
Project description:ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancer. Deficiency in its homolog ARID1B is synthetically lethal with ARID1A mutation. However, the functional relationship between these homologs has not been explored. Here we use ATAC-seq, genome-wide histone modification mapping, and expression analysis to examine colorectal cancer cells lacking one or both ARID proteins. We find that ARID1A has a dominant role in maintaining chromatin accessibility at enhancers, while the contribution of ARID1B is evident only in the context of ARID1A mutation. Changes in accessibility are predictive of changes in expression and correlate with loss of H3K4me and H3K27ac marks, nucleosome spacing, and transcription factor binding, particularly at growth pathway genes including MET. We find that ARID1B knockdown in ARID1A mutant ovarian cancer cells causes similar loss of enhancer architecture, suggesting that this is a conserved function underlying the synthetic lethality between ARID1A and ARID1B.
2017-09-29 | GSE101966 | GEO
Project description:Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons. Subplate neurons (SPNs), strategically positioned at the interface of cortical grey and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pan-cortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating non-cell autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate-thalamocortical axon co-fasciculation (“handshake”), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate-thalamocortical axon co-fasciculation and extracellular matrix assembly. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.
2021-05-06 | GSE163273 | GEO
Project description:Every known SWI/SNF chromatin-remodeling complex incorporates an ARID DNA binding domain-containing subunit. Despite being a ubiquitous component of these complexes, physiological roles for this domain remain undefined. We screened an N-ethyl-N-nitrosurea (ENU) mutagenized library for ARID domain point mutations and generated an Arid1a/Baf250a hypomorphic allele. The mutant ARID1a (V1068G) protein is stably expressed at wild-type levels, and it is capable of assembling into a SWI/SNF complex with in vitro mononucleosome disruption activity. However, its capacity to bind DNA is lost. Consistent with defective DNA binding, mutant protein occupancy at known SWI/SNF target genes is decreased. Loss of DNA binding is associated with concurrent changes in SWI/SNF target gene expression. Mutant embryos manifest heart defects, fail to establish proper yolk sac vasculature, and exhibit hemorrhaging. As a result of these phenotypes, mutant embryos fail to establish proper circulation, culminating in ischemic arrest in utero between days 9.5 and 11.5. These data support a role for ARID1a-containing, BAF-A complexes in heart and extraembryonic vascular development, and indicate the ARID domain of ARID1a is essential in this regard. Hence, intrinsic ARID subunit-DNA interactions are required for normal SWI/SNF function in vivo. Four-condition experiment, wild-type vs Baf250a/Arid1a^V1068G/V1068G yolk sacs isolated at E8.5 and E9.5. Biological replicates: 3 per condition.
2012-01-15 | E-GEOD-32116 | biostudies-arrayexpress