title: Polycomb Repressive Complex 2 Confers BRG1 Dependency on the CIITA Locus.
abstract: CIITA (or MHC2TA) coordinates constitutive and IFN-γ-induced expression of MHC class II genes. IFN-γ responsiveness of CIITA requires BRG1 (SMARCA4), the ATPase engine of the chromatin remodeling SWI/SNF complex (also called BAF). SWI/SNF is defective in many human cancers, providing a mechanism to explain IFN-γ resistance. BRG1 dependency is mediated through remote elements. Short CIITA reporters lacking these elements respond to IFN-γ, even in BRG1-deficient cells, suggesting that BRG1 counters a remote repressive influence. The nature of this distal repressor is unknown, but it would represent a valuable therapeutic target to reactivate IFN-γ responsiveness in cancer. In this article, we show that the polycomb repressive complex 2 (PRC2) components EZH2 and SUZ12, as well as the associated histone mark H3K27me3, are codetected at interenhancer regions across the CIITA locus. IFN-γ caused a BRG1-dependent reduction in H3K27me3, associated with nucleosome displacement. SUZ12 knockdown restored IFN-γ responsiveness in BRG1-null cells, and it mimicked the ability of BRG1 to induce active histone modifications (H3K27ac, H3K4me) at the -50-kb enhancer. Thus, PRC2 confers BRG1 dependency on the CIITA locus. Our data suggest that, in addition to its known roles in promoting stemness and proliferation, PRC2 may inhibit immune surveillance, and it could be targeted to reactivate CIITA expression in SWI/SNF deficient cancers.
authors: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G1X5, Canada;
authors: Mohamed
authors: M
authors: Abou El Hassan
authors: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G1X5, Canada;
authors: Tao
authors: T
authors: Yu
authors: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G1X5, Canada;
authors: Lan
authors: L
authors: Song
authors: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G1X5, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario M5T 3A9, Canada bremner@lunenfeld.ca.
authors: Rod
authors: R
authors: Bremner
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004265:DNA Helicases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D056426:Genetic Loci; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2; C084108:SMARCA4 protein, human; D004265:DNA Helicases