  Enhancers play a central role in cell-type-specific gene expression and are
marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However,
the methyltransferases responsible for H3K4me1/2 on enhancers remain elusive.
Furthermore, how these enzymes function on enhancers to regulate
cell-type-specific gene expression is unclear. Here we identify MLL4 (KMT2D) as
a major mammalian H3K4 mono- and di-methyltransferase with partial functional
redundancy with MLL3 (KMT2C). Using adipogenesis and myogenesis as model
systems, we show that MLL4 exhibits cell-type- and
differentiation-stage-specific genomic binding and is predominantly localized
on enhancers. MLL4 co-localizes with lineage-determining transcription factors
(TFs) on active enhancers during differentiation. Deletion of MLL4 markedly
decreases H3K4me1/2, H3K27ac, Polymerase II and Mediator levels on enhancers
and leads to severe defects in cell-type-specific gene expression and cell
differentiation. Together, these findings identify MLL4 as a major mammalian
H3K4 mono- and di-methyltransferase essential for enhancer activation during
cell differentiation.
