Function of MLL4 in mouse embryonic stem cells and somatic cell reprogramming. Mus musculus

Enhancers control cell type-specific gene expression and direct cell fate transition. Enhancers are marked by H3K4me1/2. MLL4 (KMT2D) is a major enhancer H3K4me1/2 methyltransferase. Here we show in embryonic stem cells (ESCs), MLL4 associates with, but is dispensable for the maintenance of, active enhancers of ESC identity genes. As a result, MLL4 is dispensable for cell identity gene expression and self-renewal in ESCs. In contrast, MLL4 is essential for activation of de novo enhancers and induction of cell identity genes during ESC differentiation. Similarly, MLL4 is dispensable for maintaining fibroblast cell identity but is essential for reprogramming into induced pluripotent stem cells. These results indicate that while MLL4 is dispensable for maintaining cell identity, it controls cell fate transitions by orchestrating de novo enhancer activation. Overall design: MLL3-/-;MLL4flox/fox and MLL3-/-;MLL4-/- mouse embryonic stem cells(ESCs) are generated. ChIP-Seq of histone modificaitons, MLL4 and RNA-Seq are performed in undifferentiated ESCs and day4 differentiated embryoid bodies (D4EB). MLL3-/-;MLL4flox/fox and MLL3-/-;MLL4-/- immortalized mouse embryonic fibroblasts(MEFs) are reprogrammed with lentiviral infection of OSKM. RNA-Seq are performed in MEFs and day20 programmed cells.