KMT2D

Last updated
KMT2D
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases KMT2D , ALR, KABUK1, MLL2, MLL4, lysine methyltransferase 2D, histone-lysine methyltransferase 2D, TNRC21, AAD10, KMS, CAGL114
External IDs OMIM: 602113 MGI: 2682319 HomoloGene: 86893 GeneCards: KMT2D
Orthologs
SpeciesHumanMouse
Entrez

8085

381022

Ensembl

ENSG00000167548

ENSMUSG00000048154

UniProt

O14686

Q6PDK2

RefSeq (mRNA)

NM_003482

NM_001033276
NM_001033388

RefSeq (protein)

NP_003473

NP_001028448

Location (UCSC) Chr 12: 49.02 – 49.06 Mb Chr 15: 98.73 – 98.77 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. [5] It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A (or MLL1), KMT2B (or MLL2), KMT2C (or MLL3), KMT2F (or SET1A), and KMT2G (or SET1B).

Contents

KMT2D is a large protein over 5,500 amino acids in size and is widely expressed in adult tissues. [6] The protein co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development. [5] It also plays critical roles in regulating cell fate transition, [5] [7] [8] [9] metabolism, [10] [11] and tumor suppression. [12] [13] [14] [15]

Mutations in KMT2D cause human genetic conditions including Kabuki syndrome, [16] another distinct congenital malformations disorder [17] and various forms of cancer. [18]

Structure

Gene

In mice, KMT2D is coded by the Kmt2d gene located on chromosome 15F1. Its transcript is 19,823 base pairs long and contains 55 exons and 54 introns. [19]

In humans, KMT2D is coded by the KMT2D gene located on chromosome 12q13.12. It's transcript is 19,419 base pairs long and contains 54 exons and 53 introns. [20]

Protein

KMT2D is homologous to Trithorax-related (Trr), which is a Trithorax-group protein. [21] The mouse and human KMT2D proteins are 5,588 and 5,537 amino acids in length, respectively. Both species of the protein weigh about 600 kDa. [19] [20] KMT2D contains an enzymatically active C-terminal SET domain that is responsible for its methyltransferase activity and maintaining protein stability in cells. [22] Near the SET domain are a plant homeotic domain (PHD) and FY-rich N/C-terminal (FYRN and FYRC) domains. The protein also contains six N-terminal PHDs, a high mobility group (HMG-I), and nine nuclear receptor interacting motifs (LXXLLs). [18] It was shown that amino acids Y5426 and Y5512 are critical for the enzymatic activity of human KMT2D in vitro. [23] In addition, mutation of Y5477 in mouse KMT2D, which corresponds to Y5426 in human KMT2D, resulted in the inactivation of KMT2D's enzymatic activity in embryonic stem cells. [24] Depletion of cellular H3K4 methylation reduces KMT2D levels, indicating that the protein's stability could be regulated by cellular H3K4 methylation. [23]

Protein complex

Several components of the KMT2D complex were first purified in 2003, [25] and then the entire complex was identified in 2007. [26] [27] [28] [29] Along with KMT2D, the complex also contains ASH2L, RbBP5, WDR5, DPY30, NCOA6, UTX (also known as KDM6A), PA1, and PTIP. WDR5, RbBP5, ASH2L, and DPY30 form the four-subunit sub-complex WRAD, which is critical for H3K4 methyltransferase activity in all mammalian Set1-like histone methyltransferase complexes. [30] WDR5 binds directly with FYRN/FYRC domains of C-terminal SET domain-containing fragments of human KMT2C and KMT2D. [26] UTX, the complex’s H3K27 demethylase, PTIP, and PA1 are subunits that are unique to KMT2C and KMT2D. [26] [31] [32] KMT2D acts as a scaffold protein within the complex; absence of KMT2D results in destabilization of UTX and collapse of the complex in cells. [5] [23]

Enhancer regulation

KMT2D is a major enhancer mono-methyltransferase and has partial functional redundancy with KMT2C. [5] [7] The protein selectively binds enhancer regions based on type of cell and stage of differentiation. During differentiation, lineage determining transcription factors recruit KMT2D to establish cell-type specific enhancers. For example, CCAAT/enhancer-binding protein β (C/EBPβ), an early adipogenic transcription factor, recruits and requires KMT2D to establish a subset of adipogenic enhancers during adipogenesis. Depletion of KMT2D prior to differentiation prevents the accumulation of H3K4 mono-methylation (H3K4me1), H3K27 acetylation, the transcriptional coactivator Mediator, and RNA polymerase II on enhancers, resulting in severe defects in gene expression and cell differentiation. [5] KMT2C and KMT2D also identify super-enhancers and are required for formation of super-enhancers during cell differentiation. [33] Mechanistically, KMT2C and KMT2D are required for the binding of H3K27 acetyltransferases CREB-binding protein (CBP) and/or p300 on enhancers, enhancer activation, and enhancer-promotor looping prior to gene transcription. [5] [33] The KMT2C and KMT2D proteins, rather than the KMT2C and KMT2D-mediated H3K4me1, control p300 recruitment to enhancers, enhancer activation, and transcription from promoters in embryonic stem cells. [7]

Functions

Development

Whole-body knockout of Kmt2d in mice results in early embryonic lethality. [5] Targeted knockout of Kmt2d in precursors cells of brown adipocytes and myocytes results in decreases in brown adipose tissue and muscle mass in mice, indicating that KMT2D is required for adipose and muscle tissue development. [5] In the hearts of mice, a single copy of the Kmt2d gene is sufficient for normal heart development. [34] Complete loss of Kmt2d in cardiac precursors and myocardium leads to severe cardiac defects and early embryonic lethality. KMT2D mediated mono- and di-methylation is required for maintaining necessary gene expression programs during heart development. Knockout studies in mice also show that KMT2D is required for proper B-cell development. [12]

Cell fate transition

KMT2D is partially functionally redundant with KMT2C and is required for cell differentiation in culture. [5] [7] KMT2D regulates the induction of adipogenic and myogenic genes and is required for cell-type specific gene expression during differentiation. KMT2C and KMT2D are essential for adipogenesis and myogenesis. [5] Similar functions are seen in neuronal and osteoblast differentiation. [8] [9] KMT2D facilitates cell fate transition by priming enhancers (through H3K4me1) for p300-mediated activation. For p300 to bind the enhancer, the physical presence of KMT2D, and not just the KMT2D-mediated H3K4me1, is required. However, KMT2D is dispensable for maintaining embryonic stem cell and somatic cell identity. [7]

Metabolism

KMT2D is partially functionally redundant with KMT2C in the liver as well. Heterozygous Kmt2d+/- mice exhibit enhanced glucose tolerance and insulin sensitivity and increased serum bile acid. [10] KMT2C and KMT2D are significant epigenetic regulators of the hepatic circadian clock and are co-activators of the circadian transcription factors retinoid-related orphan receptor (ROR)-α and -γ. [10] In mice, KMT2D also acts as a coactivator of PPARγ within the liver to direct over-nutrition induced steatosis. Heterozygous Kmt2d+/- mice exhibit resistance to over-nutrition induced hepatic steatosis. [11]

Tumor suppression

KMT2C and KMT2D along with NCOA6 act as coactivators of p53, a well-established tumor suppressor and transcription factor, and are necessary for endogenous expression of p53 in response to doxorubicin, a DNA damaging agent. [13] KMT2C and KMT2D have also been implicated with tumor suppressor roles in acute myeloid leukemia, follicular lymphoma, and diffuse large B cell lymphoma. [12] [14] [15] Knockout of Kmt2d in mice negatively affects the expression of tumor suppressor genes TNFAIP3, SOCS3, and TNFRSF14. [15]

Conversely, KMT2D deficiency in several breast and colon cancer cell lines leads to reduced proliferation. [35] [36] [37] Increased KMT2D was shown to facilitate chromatin opening and recruitment of transcription factors, including estrogen receptor (ER), in ER-positive breast cancer cells. [38] Thus, KMT2D may have diverse effects on tumor suppression in different cell types.

Clinical significance

Germline heterozygous loss of function mutations in KMT2D, also known as MLL2 in humans, cause Kabuki syndrome type 1 [16] with mutational occurrence rates between 56% and 75%. [39] [40] [41] [42] Mosaic mutations and intragenic deletions and duplications have also been described in this condition. [43] Type 1 Kabuki syndrome is characterised by developmental delay, intellectual disability, postnatal dwarfism, recognizable facial dysmorphism (reminiscent of the make-up of actors of Kabuki theatre), a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy. [44] Note that variants in a functionally related gene, KDM6A, cause Kabuki syndrome type 2 that is an X-linked condition, shares several clinical features with Kabuki syndrome type 1 but phenotypically is a much more variable condition. [45]

Germline heterozygous missense variants in exon 38 or 39 of the KMT2D gene cause another rare distinct multiple malformation disorder characterized by choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. [17]

Congenital heart disease has been associated with an excess of mutations in genes that regulate H3K4 methylation, including KMT2D. [46]

Somatic frameshift and nonsense mutations in the SET and PHD domains affect 37% and 60%, respectively, of the total KMT2D mutations in cancers. [18] Cancers with somatic mutations in KMT2D occur most commonly in the brain, lymph nodes, blood, lungs, large intestine, and endometrium. [18] These cancers include medulloblastoma, [47] [48] [49] pheochromocytoma, [50] non-Hodgkin lymphomas, [51] cutaneous T-cell lymphoma, Sézary syndrome, [52] bladder, lung, and endometrial carcinomas, [53] esophageal squamous cell carcinoma, [54] [55] [56] pancreatic cancer, [57] and prostate cancer. [58]

Note

Related Research Articles

<span class="mw-page-title-main">Histone methyltransferase</span> Histone-modifying enzymes

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code. Histones associate with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. For details of gene expression regulation by histone modifications see table below.

Demethylases are enzymes that remove methyl (CH3) groups from nucleic acids, proteins (particularly histones), and other molecules. Demethylases are important epigenetic proteins, as they are responsible for transcriptional regulation of the genome by controlling the methylation of DNA and histones, and by extension, the chromatin state at specific gene loci.

<span class="mw-page-title-main">KDM1A</span> Protein-coding gene in the species Homo sapiens

Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein that in humans is encoded by the KDM1A gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysine 4 (H3K4). Other reported methylated lysine substrates such as histone H3K9 and TP53 have not been biochemically validated. This enzyme plays a critical role in oocyte growth, embryogenesis, hematopoiesis and tissue-specific differentiation. LSD1 was the first histone demethylase to be discovered though more than 30 have since been described.

<span class="mw-page-title-main">DNMT3B</span> Protein-coding gene in the species Homo sapiens

DNA (cytosine-5)-methyltransferase 3 beta, is an enzyme that in humans in encoded by the DNMT3B gene. Mutation in this gene are associated with immunodeficiency, centromere instability and facial anomalies syndrome.

<span class="mw-page-title-main">EZH2</span> Protein-coding gene in the species Homo sapiens

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

<span class="mw-page-title-main">H3F3A</span> Gene for histone H3.3 protein

Histone H3.3 is a protein that in humans is encoded by the H3F3A and H3F3B genes. It plays an essential role in maintaining genome integrity during mammalian development.

<span class="mw-page-title-main">DNA (cytosine-5)-methyltransferase 3A</span> Protein-coding gene in the species Homo sapiens

DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the DNMT3A gene.

<span class="mw-page-title-main">KMT2A</span> Protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase 2A, also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia1 (MLL1), or zinc finger protein HRX (HRX), is an enzyme that in humans is encoded by the KMT2A gene.

<span class="mw-page-title-main">SETDB1</span> Enzyme-coding gene in humans

Histone-lysine N-methyltransferase SETDB1 is an enzyme that in humans is encoded by the SETDB1 gene. SETDB1 is also known as KMT1E or H3K9 methyltransferase ESET.

<span class="mw-page-title-main">KMT2C</span> Protein-coding gene in the species Homo sapiens

Lysine N-methyltransferase 2C (KMT2C) also known as myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3) is an enzyme that in humans is encoded by the KMT2C gene.

<span class="mw-page-title-main">SETMAR</span> Protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase SETMAR is an enzyme that in humans is encoded by the SETMAR gene.

<span class="mw-page-title-main">SMYD3</span> Protein-coding gene in the species Homo sapiens

SET and MYND (myeloid-Nervy-DEAF-1) domain-containing protein 3 is a protein that in humans is encoded by the SMYD3 gene.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.

H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies.

H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono-methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for genome integrity including DNA damage repair, DNA replication and chromatin compaction.

H3K36me is an epigenetic modification to the DNA packaging protein Histone H3, specifically, the mono-methylation at the 36th lysine residue of the histone H3 protein.

References

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