The polycomb repressive complex 2 (PRC2) catalyzes the methylation of histone H3 on lysine 27 (H3K27) to generate trimethyl-H3K27 (H3K27me3) marks,thereby leading to a repressive chromatin state that inhibits gene expression.C10ORF12 was recently identified as a novel PRC2 interactor.Here,we show that C10ORF12 specifically interacts with PRC2 through its middle region (positions 619-718).C10ORF12 significantly enhances the histone methyltransferase activity of PRC2 in vitro and dramatically increases the total H3K27me3 levels in HeLa cells.C10ORF12 also antagonizes Jarid2,which is an auxiliary factor of the PRC2.2 subcomplex,to promote increased H3K27me3 levels in HeLa cells.Moreover,C10ORF12 alters the substrate preference of PRC2.These results indicate that C10ORF12 functions as a positive regulator of PRC2 and facilitates PRC2-mediated H3K27me3 modification of chromatin.These findings provide new insight into the roles of C10ORF12 in regulating the activity of the PRC2 complex.