Interferon-gamma-induced chromatin remodeling at the CIITA locus is BRG1 dependent.
SWI/SNF regulates growth control, differentiation and tumor suppression, yet few direct targets of this chromatin-remodeling complex have been identified in mammalian cells. We report that SWI/SNF is required for interferon (IFN)-gamma induction of CIITA, the master regulator of major histocompatibility complex class II expression. Despite the presence of functional STAT1, IRF-1 and USF-1, activators implicated in CIITA expression, IFN-gamma did not induce CIITA in cells lacking BRG1 and hBRM, the ATPase subunits of SWI/SNF. Reconstitution with BRG1, but not an ATPase-deficient version of this protein (K798R), rescued CIITA induction, and enhanced the rate of induction of the IFN-gamma-responsive GBP-1 gene. Not ably, BRG1 inhibited the CIITA promoter in transient transfection assays, underscoring the importance of an appropriate chromosomal environment. Chromatin immunoprecipitation revealed that BRG1 interacts directly with the endogenous CIITA promoter in an IFN-gamma-inducible fashion, while in vivo DNase I footprinting and restriction enzyme accessibility assays showed that chromatin remodeling at this locus requires functional BRG1. These data provide the first link between a cytokine pathway and SWI/SNF, and suggest a novel role for this chromatin-remodeling complex in immune surveillance.
Pattenden
Samantha G
SG
Molecular and Cellular Division, Toronto Western Research Institute, Department of Ophthalmology and Visual Science, University of Toronto, Toronto, Canada M5T 2S8.
Klose
Robert
R
Karaskov
Elizabeth
E
Bremner
Rod
R
D002461:Cell Line, Transformed; D002843:Chromatin / Q000502:physiology*; D004265:DNA Helicases; D005786:Gene Expression Regulation; D006367:HeLa Cells; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002843:Chromatin; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D007371:Interferon-gamma; C084108:SMARCA4 protein, human; D004265:DNA Helicases