Epigenetic Regulation of the Class II Transactivator (CIITA) by the Polycomb Repressive Complex 2 (PRC2)

Major Histocompatibility Class II (MHC II) molecules present extracellular peptides to T helper cells and are thus responsible for initiating, regulating, and terminating immune responses to foreign agents and tumors. Expression of MHC II is induced by the inflammatory cytokine interferon gamma (IFN‐γ) which induces transcription of the Class II Transactivator (CIITA), the master regulator of MHC II genes. Transcription of CIITA through the IFN‐γ inducible CIITA promoter IV is frequently suppressed in tumor cells through specific trimethylation of histone H3 lysine 27 (H3K27me3) by the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2). EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2); however the mechanisms of recruitment of PRC2 to mammalian promoters remains unknown as proteins in the PRC2 complex contain no DNA binding domains. We identify here two EZH2 binding partners which bind DNA and regulate PRC2 recruitment to CIITApIV. We demonstrate that Yin Yang 1 (YY1), the homolog of the Drosophila PRC2 recruiting protein Pleiohomoeotic (Pho), and Jumonji domain containing protein 2 (JARID2), a member of histone demethylase family, both interact with EZH2. Upon IFN‐γ stimulation, YY1 dissociates from CIITA pIV while Jarid2 CIITA pIV binding increases, suggesting novel roles for each of these proteins in regulating inducible gene promoter dynamics. Research supported by grants from the American Cancer Society, the Georgia Cancer Coalition, and the Georgia Research Alliance (to S.F. Greer).