NIH Research Festival
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 is unclear. Here we identify MLL4 as a major H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3. 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 TFs on active enhancers during differentiation. Deletion of MLL4 markedly decreases H3K4me1/2, H3K27ac, and PolII levels on enhancers and leads to severe defects in differentiation. Together, these findings identify MLL4 as a major H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation. Our data suggest a step-wise model of enhancer activation. Step 1, pioneer TFs bind enhancer-like regions. Step 2, enhancer commissioning by MLL4. Pioneer TFs cooperatively recruit MLL4 to perform H3K4me1/2 on enhancer-like regions. Step 3, enhancer activation by H3K27 acetyltransferases CBP/p300, followed by PolII recruitment, establishment of enhancer–promoter interaction, and activation of cell-type-specific gene expression. Our unpublished data in embryonic stem cells show that MLL4 co-localizes with core circuitry TFs Oct4, Sox2 and Nanog on active ESC enhancers. Interestingly, MLL4 is dispensable for ESC self-renewal, likely due to the functional redundancy with other H3K4me1/2 methyltransferases. However, by regulating de novo enhancer activation, MLL4 is essential not only for ESC differentiation but also for somatic cell reprogramming into ESC-like iPS cells.
Scientific Focus Area: Chromosome Biology
This page was last updated on Friday, March 26, 2021