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ARID1A deficiency weakens BRG1-RAD21 interaction that jeopardizes chromatin compactness and drives HCC metastasis [RNA-seq]

ABSTRACT: ARID1A, encoding a subunit of SWI/SNF chromatin remodeling complex, is widely recognized as a tumor suppressor gene in multiple tumor types including hepatocellular carcinoma (HCC). Previous studies have demonstrated that ARID1A deficiency can cause HCC metastasis, possibly due to the altered chromatin organization, however the underlying mechanisms of which remain poorly understood. Whether and how SWI/SNF complex could function as an architectural cooperator to synergistically stabilize chromatin organization should be explored, particular in tumorigenesis. Here we reveal that SWI/SNF complex acts as a potential architectural cooperator via BRG1-RAD21 axis for chromatin organization maintenance; ARID1A deficiency weakens the interaction and thus loosens chromatin compactness, which drives HCC metastasis dependent on the conformational dysregulation on some key genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE152050 | GEO | 2020/08/24

REPOSITORIES: GEO

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ARID1A deficiency weakens BRG1-RAD21 interaction that jeopardizes chromatin compactness and drives HCC metastasis [ChIP-seq]

Project description:ARID1A, encoding a subunit of SWI/SNF chromatin remodeling complex, is widely recognized as a tumor suppressor gene in multiple tumor types including hepatocellular carcinoma (HCC). Previous studies have demonstrated that ARID1A deficiency can cause HCC metastasis, possibly due to the altered chromatin organization, however the underlying mechanisms of which remain poorly understood. Whether and how SWI/SNF complex could function as an architectural cooperator to synergistically stabilize chromatin organization should be explored, particular in tumorigenesis. Here we reveal that SWI/SNF complex acts as a potential architectural cooperator via BRG1-RAD21 axis for chromatin organization maintenance; ARID1A deficiency weakens the interaction and thus loosens chromatin compactness, which drives HCC metastasis dependent on the conformational dysregulation on some key genes.

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ARID1A regulates condensin II distribution and chromosomal partition [ChIP-seq]

Project description:ARID1A, a subunit of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, influences gene accessibility. However, the role of ARID1A in spatial genomic organization and chromosomal interaction remains elusive. We showed that the SWI/SNF complex interacts with condensin II and they show significant overlapping distributions in enhancers. ARID1A inactivation drives redistribution of condensin II preferentially at enhancers without affecting the interaction between the SWI/SNF and condensing II complexes. ARID1A and condensin II contribute to transcriptionally inactive B compartments, while ARID1A weakens the borders of topologically associated domains. ARID1A inactivation decreases the frequency of genomic interactions over distance, but increases the intermixing of interphase small chromosomes, which was validated by three dimensional chromosome painting. These results demonstrated ARID1A spatially partitions genome and chromosomes.

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ARID-DNA interactions are essential for SWI/SNF function

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.

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Exploring the interaction between the SWI/SNF chromatin remodeling complex and the zinc finger factor CTCF

Project description:The transcription factor CCCTC-binding factor (CTCF) modulates pleiotropic functions mostly related to gene expression regulation. The role of CTCF in large scale genome organization is also well established. A unifying model to explain relationships between many CTCF-mediated activities involve direct or indirect interactions with numerous protein cofactors recruited to specific binding sites. The co-association of CTCF with other architectural proteins such as cohesin, chromodomain helicases and BRG1 further support the interplay between master regulators of mammalian genome folding. Here we report a comprehensive LC-MS/MS mapping of the components of the SWI/SNF chromatin remodeling complex co-associated with CTCF including subunits belonging to the core, signature and ATPase modules. We further show that the localization patterns of representative SWI/SNF members significantly overlap with CTCF sites on transcriptionally active chromatin regions. Moreover, we provide evidence of a direct binding of the BRK-BRG1 domain to the zinc finger motifs 4-8 of CTCF, thus suggesting that these domains mediate the interaction of CTCF with the SWI/SNF complex. These findings provide an updated view of the cooperative nature between CTCF and the SWI/SNF ATP-dependent chromatin-remodeling complexes, an important step for understanding how these architectural proteins collaborate to shape the genome.

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Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells [RNA-seq]

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Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells [ChIP-seq]

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ChIP-seq analysis of Arid1a and C/ebpÎ± in the mouse livers

Project description:Arid1a is the subunit of SWI/SNF complex, which was reported to guide SWI/SNF to DNA. Here, we found that loss of Arid1a in the liver and other adult tissues results in improved organ regeneration. Within SWI/SNF complexes, Arid1a physically interacts with C/ebpÎ±, a hepatocyte transcription factor that drives maturation and limits proliferation. Genome-wide analysis showed that loss of Arid1a reduces the recruitment and activity of C/ebpÎ± on target promoters, resulting in expression programs that favor regeneration and cellular fitness during injury. Arid1a binding is enriched in promoters near transcriptional start sites (TSSs), and C/ebpÎ± binds at precisely the same positions, indicating that Arid1a facilitates C/ebpÎ± binding across the genome. Perfuse and isolate primary hepatocytes from mice livers, analysis of genomic occupancy of C/ebpÎ± and H3K4me2 in hepatocytes from Arid1a WT and Arid1a liver specific KO mice by ChIP-seq. Analysis of genomic occupancy of Arid1a in the hepatocytes from V5-Arid1a transgenic mouse by ChIP-seq.

2016-03-30 | E-GEOD-65167 | biostudies-arrayexpress

Therapeutic targeting glutamine dependence in SWI/SNF-inactivated cancers

Project description:Alterations in components of the SWI/SNF chromatin-remodeling complex occur in ~20% of all human cancers. For example, ARID1A is mutated in up to 62% of clear cell ovarian carcinoma (OCCC), a disease currently lacking effective therapies. Here we show that ARID1A mutation creates a dependence on glutamine metabolism. SWI/SNF represses glutaminase I (GLS1) and ARID1A inactivation upregulates GLS1. ARID1A inactivation increases glutamine utilization and metabolism through the tricarboxylic acid cycle to support aspartate synthesis. Indeed, glutaminase inhibitor CB-839 suppresses the growth of ARID1A mutant, but not wildtype, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PDL1 antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation. Our data indicate that pharmacological inhibition of glutaminase alone or in combination with immune checkpoint blockade represents a novel therapeutic strategy for cancers involving alterations in the SWI/SNF complex such as ARID1A mutations.

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