BRG1-mediated chromatin remodeling regulates differentiation and gene expression of T helper cells.
During T helper cell differentiation, distinct programs of gene expression play a key role in defining the immune response to an environmental challenge. How chromatin remodeling events at the associated cytokine loci control differentiation is not known. We found that the ATP-dependent remodeling enzyme subunit BRG1 was required for T helper 2 (Th2) differentiation and Th2 cytokine transcription. BRG1 binding to cytokine genes was regulated by the extent of differentiation, the extent of activation, and cell fate. BRG1 was required for some features of the chromatin structure in target genes (DNase I hypersensitivity and histone acetylation), suggesting that BRG1 remodeling activity was directly responsible for changes in gene expression. NFAT and STAT6 activity were required for BRG1 recruitment to the Th2 locus control region, and STAT6 associated with BRG1 in a differentiation-inducible manner, suggesting direct recruitment of BRG1 to the bound loci. Together, these findings suggest BRG1 interprets differentiation signals and plays a causal role in gene regulation, chromatin structure, and cell fate.
Wurster
Andrea L
AL
Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Pazin
Michael J
MJ
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D042002:Chromatin Assembly and Disassembly; D016207:Cytokines / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C511511:Arid1a protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D014157:Transcription Factors; D000251:Adenosine Triphosphatases; C513194:Smarca4 protein, mouse; D004265:DNA Helicases