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 5,500 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.

Molecular characteristics of terminal deoxynucleotidyl transferase negative precursor B‐cell phenotype Burkitt leukemia with IGH‐MYC rearrangement

“…KMT2D is a chromatin modifying gene that catalyzes mono-and demethylation of H3K4 at enhancer regions 13 plasm with precursor B-cell phenotype, that is, the IGH-MYC rearrangement occurred from an aberrant VDJ rearrangement, lack of mutations in genes recurrently mutated in BL, and 1q gain. KMT2D is a chromatin modifying gene that catalyzes mono-and demethylation of H3K4 at enhancer regions 13 plasm with precursor B-cell phenotype, that is, the IGH-MYC rearrangement occurred from an aberrant VDJ rearrangement, lack of mutations in genes recurrently mutated in BL, and 1q gain.…”

PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression

“…KMT2D (also known as MLL2 or MLL4) is a member of the COMPASS (Complex Of Proteins Associated with Set1) family and has been identified as a major histone methyltransferase that activates transcription via mono- and di-methylation of histone 3 at lysine 4 (H3K4), which are active chromatin marks found mainly at enhancers (Froimchuk et al, 2017; Hu et al, 2013). Hence, KMT2D is essential for enhancer activation and transcriptional output.…”

Somatic genetic alterations in synchronous and metachronous low‐grade serous tumours and high‐grade carcinomas of the adnexa

“…The low‐grade and high‐grade tumours in cases 2 and 3 harboured likely pathogenic alterations in genes involved in chromatin remodelling, including: SETD2 and KMT2D (which mediate methylation of histone H3); EP300 (responsible, in conjunction with CREBBP , for acetylation of histone H3); SMARCA4 (a component of the SWI/SNF complex); and SPOP (which encodes an E3 ubiquitin ligase protein). Ovarian tumours that commonly show alterations in chromatin‐remodelling genes include clear cell and endometrioid carcinomas, and small cell carcinomas of hypercalcaemic type .…”