The Class II Transactivator (CIITA), is the master regulator of Major Histocompatibility Class II (MHC II) genes. Transcription of CIITA is characterized by a decrease in specific trimethylation of histone H3 lysine 27 (H3K27me3), catalyzed by the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2). While EZH2 is the known catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and is present at the inactive CIITA promoter; the mechanisms of recruitment of PRC2 to mammalian promoters remains unknown. Here we identify two DNA-binding proteins, YY1 and Jarid2, which interact with and regulate PRC2 recruitment to CIITA promoters. Our study is the first to identify novel roles of YY1 and Jarid2 in the epigenetic regulation of a mammalian gene by the PRC2.