title: 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.
authors.affiliation: Department of Genetics, Carolina Center for Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Chandler
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brennan
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Schisler
authors.forename: Daniel
authors.initials: D
authors.lastname: Serber
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Terry
authors.initials: T
authors.lastname: Magnuson
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D002843:Chromatin / Q000737:chemistry; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D019295:Computational Biology; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: C511511:Arid1a protein, mouse; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009707:Nucleosomes; D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D014157:Transcription Factors; D004247:DNA