Elsevier

Gene

Volume 627, 5 September 2017, Pages 337-342
Gene

Gene wiki review
Histone H3 lysine 4 methyltransferase KMT2D

https://doi.org/10.1016/j.gene.2017.06.056Get rights and content

Highlights

  • KMT2D is a major enhancer H3K4 mono-methyltransferase.

  • KMT2D is required for enhancer activation and cell type-specific gene expression.

  • KMT2D regulates development, differentiation, metabolism, and tumor suppression.

  • KMT2D mutations are associated with developmental diseases and various cancers.

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.

Introduction

Epigenetic mechanisms play critical roles in regulating gene expression. Methylation of histone H3 lysine 4 (H3K4) is one method that cells use to mark promoters and enhancers. Active promoters are marked with tri-methylation of H3K4 (H3K4me3) while enhancers are marked with mono- and di-methylation of H3K4 (H3K4me1 and H3K4me2, respectively) (Calo and Wysocka, 2013, Heintzman et al., 2007). In yeast, the SET1 enzymatic subunit of the Set1 complex accounts for all mono-, di- and tri-methylations on histone H3K4 (Roguev et al., 2001, Ruthenburg et al., 2007). In Drosophila, there are three Set1-like H3K4 methyltransferase complexes with three different enzymatic subunits responsible for their H3K4 methyltransferase activity: dSet1, Trithorax (Trx), and Trithorax-related (Trr). dSet1 is responsible for the bulk of the H3K4me3 while Trr was shown to regulate H3K4me1 (Ardehali et al., 2011, Mohan et al., 2011). As shown in Fig. 1, mammals have six Set1-like H3K4 methyltransferases: KMT2A (or MLL1), KMT2B (or MLL2), KMT2C (or MLL3), KMT2D (or MLL4, ALR, and sometimes MLL2), KMT2F (or SET1A), and KMT2G (or SET1B). Based on the sequence homology of the SET-containing enzymatic subunits, it was determined that KMT2A and KMT2B are homologous to Trx, KMT2C and KMT2D are homologous to Trr, and KMT2F and KMT2G are homologous to dSet1 (Mohan et al., 2011). Consistent with dSet1's role in Drosophila, it was shown that depletion of KMT2F/G's unique CFP1 subunit in mammalian cells decreases global H3K4me3 levels, indicating that KMT2F/G are major H3K4 tri-methyltransferases in mammals (Clouaire et al., 2012). In addition to the KMT2 family, there are several other H3K4 methyltransferases, including SET7, SET9, SMYD3 and Meisetz (PRDM9) (Ruthenburg et al., 2007).

In this review, we will focus on KMT2D, the major mammalian histone H3K4 mono-methyltransferase. Its established importance in gene regulation and frequency of mutation in developmental diseases and cancers warrants an exploration of the literature to inspire further study and development of novel therapies. The review will mainly focus on KMT2D's effects as a H3K4 methyltransferase because non-histone substrates of KMT2D have not been identified yet. We begin with a discussion of the protein's structure and the composition of the KMT2D-associated protein complex. Then we discuss its important role as an enhancer regulator and its various functions in development, differentiation, metabolism, and tumor suppression. We conclude with a discussion of the developmental diseases and cancers that have been associated with mutations in KMT2D.

Section snippets

The KMT2D protein

In mice, the Kmt2d gene is located on chromosome 15F1. Its human ortholog is located on chromosome 12q13.12. The mouse and human transcripts are 19,823 and 19,419 base pairs long and contain 55 and 54 exons, respectively (Table 1). Sequence alignment between the cDNA of the mouse and human genes reveals that the two genes are 88% identical. The human KMT2D transcript is widely expressed in adult tissues (Prasad et al., 1997). The mouse and human KMT2D proteins are 5588 and 5537 amino acids in

The KMT2D Protein Complex

KMT2D (ALR in the cited paper) was first purified from HeLa cell nuclear extracts as a component of a protein complex (ASCOM) that also included NCOA6 (ASC-2 in the cited paper), KMT2C (HALR), ASH2L and RbBP5 (Goo et al., 2003). In a later study, affinity purification of Pax transactivation domain-interacting protein (PTIP)-associated proteins surprisingly revealed that in addition to proteins that are involved in DNA damage response, PTIP also associates with ASH2L, RbBP5, WDR5, DPY30, NCOA6,

KMT2D is a prominent enhancer H3K4 mono-methyltransferase

Enhancers are genomic regulatory elements, often bound by cell-type specific transcription factors (TFs), that are essential for cell-type specific gene expression in eukaryotic cells (Bulger and Groudine, 2011). An in depth study using adipogenesis and myogenesis as model systems firmly established that KMT2D is a prominent mammalian H3K4 mono-methyltransferase on enhancer regions and has partial functional redundancy with KMT2C (Lee et al., 2013). Studies using the KMT2D KO HCT116 human colon

KMT2D functions in development, differentiation, metabolism, and tumor suppression

KMT2D's function as a major enhancer regulator in mammalian cells translates to various biological processes, including regulation of development, differentiation, metabolism, and tumor suppression.

KMT2D mutations in developmental diseases and cancers

Loss of function mutations in KMT2D have been identified in Kabuki syndrome (Ng et al., 2010). Subsequent studies have confirmed KMT2D as a major causative gene in Kabuki syndrome with mutational occurrence rates between 56% and 75% (Bogershausen and Wollnik, 2013, Li et al., 2011, Paulussen et al., 2011). Congenital heart disease shows an excess of protein-altering mutations in genes involved in the regulation of H3K4 methylation, including KMT2D (Zaidi et al., 2013). This is consistent with

Acknowledgements

This review and the corresponding Gene Wiki article are written as part of the Gene Wiki Review series—a series resulting from a collaboration between the journal GENE and the Gene Wiki Initiative. The Gene Wiki Initiative is supported by National Institutes of Health (GM089820). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE. The authors were supported by the Intramural Research Program of the NIDDK, NIH.

The corresponding Gene Wiki entry for this review

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