The MLL4: Roles in cell differentiation, adipogenesis and cancer

Epigenetic regulation of gene expression plays an important role in cellular biological processes. MLL4 (KMT2D), as a histone lysine methyltransferase, is responsible for the mono-, di- and tri- methylation of histone 3 lysine 4 (H3K4), and H3K4me1 at the super enhancer/enhancer or promoter regions usually couples with H3K27ac to promote the expression of many genes. The biological functions of MLL4 in cell proliferation and adipogenesis have been widely reported. And silencing MLL4 prevent the development of obesity and fatty liver, making it a potential target. Furthermore, MLL4 is frequently mutated and loses the methyltransferase activity in multiple cancers. Dual functions of MLL4 in cancer have been reported due to the broad widely distribution of H3K4 in chromatin. The paradoxical functions of MLL4 complicate it as the potential target of cancer therapy. Notably, MLL4 may be a biomarker for drug sensitivity or serves as a synthetic lethal gene for specific anti-cancer agents. In this review, we examine the protein structural features of MLL4, discuss the MLL4 action in cell differentiation, adipogenesis, and cancer, and identify current challenges for future investigations.