ARID1a-DNA Interactions Are Required for Promoter Occupancy by SWI/SNF

Abstract

Every known SWI/SNF chromatin-remodeling complex incorporates an ARID DNA binding domain-containing subunit. Despite being a ubiquitous component of the complex, physiological roles for this domain remain undefined. Here, we show that disruption of ARID1a-DNA binding in mice results in embryonic lethality, with mutant embryos manifesting prominent defects in the heart and extraembryonic vasculature. The DNA binding-defective mutant ARID1a subunit is stably expressed and capable of assembling into a SWI/SNF complex with core catalytic properties, but nucleosome substrate binding and promoter occupancy by ARID1a-containing SWI/SNF complexes (BAF-A) are impaired. Depletion of ARID domain-dependent, BAF-A associations at THROMBOSPONDIN 1 (THBS1) led to the concomitant upregulation of this SWI/SNF target gene. Using a THBS1 promoter-reporter gene, we further show that BAF-A directly regulates THBS1 promoter activity in an ARID domain-dependent manner. Our data not only demonstrate that ARID1a-DNA interactions are physiologically relevant in higher eukaryotes but also indicate that these interactions facilitate SWI/SNF binding to target sites in vivo. These findings support the model wherein cooperative interactions among intrinsic subunit-chromatin interaction domains and sequence-specific transcription factors drive SWI/SNF recruitment.

Regulating the Chromatin Landscape: Structural and Mechanistic Perspectives

“…ARID, a conserved feature of SWI/SNF, can be found in the Swi1 subunit of yeast SWI/SNF and in the ARID1a and ARID1b subunits of human SWI/SNF or BAF complexes. Recent data showed that ARID in human SWI/SNF is required for binding to promoters (98). Although the SWIRM domain in SWI/SNF binds to DNA, some SWIRM domains in other complexes appear to have lost this ability (99).…”

The emerging roles of ARID1A in tumor suppression

“…This results in a decrease in promoter occupancy by SWI/SNF, and defects in cardiovascular development. 18 Since missense mutations involving the ARID domain are present in human cancers, it raises a possibility that ARID-DNA interactions are essential for the tumor suppressor function of ARID1A and loss of such interaction (due to mutations) abolishes its tumor suppression function.…”

PBRM1: A Critical Subunit of the SWI/SNF Chromatin Remodeling Complex

“…Mutation of the HSA domain prevents GR-mediated BRG1-dependent transcription. Similar, mutations within ARID domain induce defects in SWI/SNF function [ 105 ]. Mutation of V1068G in ARID1A is also homozygous lethal.…”