Protein arginine methyltransferase 6 regulates embryonic stem cell identity

Histone arginine methylation has emerged as an important histone modification involved in gene regulation. Protein arginine methyltransferase (PRMT) 4 and 5 have been shown to play essential roles in early embryonic development and in embryonic stem (ES) cells. Recently, it has been reported that PRMT6-mediated di-methylation of histone H3 at arginine 2 (H3R2me2) can antagonize tri-methylation of histone H3 at lysine 4 (H3K4me3), which marks active genes. However, whether PRMT6 and PRMT6-mediated H3R2me2 play crucial roles in early embryonic development and ES cell identity remain unclear. Here, we have investigated their roles using gain and loss of function studies with mouse ES cells as a model system. We report that Prmt6 and histone H3R2 methylation levels increased when ES cells are induced to differentiate. Consistently, we find that differentiation of ES cells upon upregulation of Prmt6 is associated with decreased expression of pluripotency genes and increased expression of differentiation markers. We also observe that elevation of Prmt6 increases the methylation level of histone H3R2 and decreases H3K4me, Chd1, and Wdr5 levels at the promoter regions of Oct4 and Nanog. Surprisingly, knockdown of Prmt6 also leads to downregulation of pluripotency genes and induction of expression of differentiation markers suggesting that Prmt6 is important for ES cell pluripotency and self-renewal. Our results indicate that a critical level of Prmt6 and histone H3R2me must be maintained in mouse ES cells to sustain their pluripotency.