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.

Properties of STAT1 and IRF1 enhancers and the influence of SNPs

“…To assess variability in ISG induction, we compiled expression data on ISGs from 7 different human cell lines or primary cells, including 5 listed in Additional file 1: Table S2, plus HeLa cells (this work) and BRG1-reconstituted SW13 cells [13]. Across all 7 cell lines there were a total of 312 ISGs, the majority (61%) were exclusively induced in only one cell type, 28% were induced in 2–4 cell types, and 11% were induced in most (5–7) cell types (Fig.…”

“…Like STAT1, IRF1 also acts as a transcription factor (TF), binding to IRF-E motifs and interferon-stimulated response elements (ISRE) [10, 11]. Access of both STAT1 and IRF1 to target enhancers requires the SWI/SNF chromatin remodeling complex to counter PRC2, which uses the histone methyl transferase EZH2 to deposit H3K27me3 and block the induction of many other cytokine and cytokine responsive loci [7, 12, 13]. IRF1 functions at the transcription initiation level by facilitating RNA Pol II recruitment to ISGs promoters [14, 15].…”

Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

“…In addition to these "intrinsic" www.aacrjournals.org pathways, our study demonstrates their "extrinsic" effects to drive lymphoma development. Previous studies showed that EZH2 mutations may mediate MHC-II expression through downregulation of CIITA, which is the master regulator of MHC-II genes (35). In addition, NLRC5 has been recently identified as a transactivator of MHC class I, which was shown to regulate MHC-I expression by reducing H3K27me3 on the MHC-I promoter (10,36).…”

Immunologic Correlates of the Abscopal Effect in a SMARCB1/INI1-negative Poorly Differentiated Chordoma after EZH2 Inhibition and Radiotherapy

“…EZH2 function impairs antigen presentation through inhibiting MHC class I and II gene expression (13,14), interferes with expression of cytokines, their receptors, and the IFNg transcriptional program (15), promotes maintenance of Treg cell identity and immunosuppressive function (11,12,16), attenuates trafficking of effector CD8 þ T cells through repression of chemokines CXCL9 and CXCL10, and impairs maturation of natural killer cells (17). Preclinically, increased EZH2 is implicated in resistance to anti-CTLA4 immunotherapy through diminished antigen presentation, which is subsequently overcome by EZH2 inhibition leading to PD-L1 downregulation and infiltration of IFNgproducing PD-1 low CD8 þ T cells (18).…”