Histone H3 lysine 4 methyltransferase KMT2D

Abstract

Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and MLL2 in humans and Mll4 in mice, belongs to a family of mammalian histone H3 lysine 4 (H3K4) methyltransferases. It is a large protein over 5500 amino acids in size and is partially functionally redundant with KMT2C. KMT2D is widely expressed in adult tissues and is essential for early embryonic development. The C-terminal SET domain is responsible for its H3K4 methyltransferase activity and is necessary for maintaining KMT2D protein stability in cells. KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. KMT2D is a major mammalian H3K4 mono-methyltransferase and co-localizes with lineage determining transcription factors on transcriptional enhancers. It is required for the binding of histone H3K27 acetyltransferases CBP and p300 on enhancers, enhancer activation and cell-type specific gene expression during differentiation. KMT2D plays critical roles in regulating development, differentiation, metabolism, and tumor suppression. It is frequently mutated in developmental diseases, such as Kabuki syndrome and congenital heart disease, and various forms of cancer. Further understanding of the mechanism through which KMT2D regulates gene expression will reveal why KMT2D mutations are so harmful and may help generate novel therapeutic approaches.

Keywords: Enhancer; Epigenetic regulation; Gene expression; H3K4 methylation; H3K4 methyltransferase; KMT2D; MLL4.

Fig. 1

The human KMT2 family of H3K4 Methyltransferases. The enzymatic SET domains are shown in blue. PHD: plant homeotic domain, HMG-I: high mobility group I, FYRC/N: FY-rich C/N-terminal, Bromo: bromodomain, RRM: RNA recognition motif, CXXC: nonmethylated-CpG DNA binding domain.

Fig. 2

The KMT2D Protein Complex. KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, DPY30), UTX, NCOA6, PA1, and PTIP in one complex. The C-terminal SET domain is the source of KMT2D’s H3K4 methyltransferase activity. UTX is the complex’s H3K27 demethylase. H3K4 methylation is associated with gene activation, whereas H3K27 methylation is associated with gene repression.

Fig. 3

Enhancer Regulation via KMT2D Priming. The proposed 3-step model through which KMT2D primes a Ppar-γ enhancer and activates cell-type specific gene expression. See text for details.