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Enhancer H3K4 methyltransferase MLL4 controls cell fate transition

Enhancers control cell type‐specific gene expression and direct cell fate transition. Enhancers are marked by H3K4me1/2. We have shown previously that MLL4 (KMT2D) is a major enhancer H3K4me1/2 methyltransferase with partial functional redundancy with MLL3 (KMT2C). However, the role of MLL4 in enhancer regulation and cell fate transition is poorly understood. 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. Together with our findings in adipocytes and naïve CD4+ T cells, these results indicate that whileMLL4 is dispensable for maintaining cell identity, it controls cell fatetransitions by orchestrating de novoenhancer activation.