SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (myeloid-Nervy-DEAF-1) domain-containing protein 3 is a protein that in humans is encoded by the SMYD3 gene. [5]
SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (myeloid-Nervy-DEAF-1) domain-containing protein 3 is a protein that in humans is encoded by the SMYD3 gene. [5]
SMYD3 is a lysine methyltransferase [6] which specifically methylates H3K4 and H4K5. [7] SMYD3 plays a role in transcriptional regulation as a member of an RNA polymerase complex. [5] It is also involved in cancer regulation. [6]
SMYD3 is predominantly expressed in skeletal muscles and the testis.
| Characteristic | Phenotype |
|---|---|
| Homozygote viability | Normal |
| Body weight | Normal |
| Anxiety | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Hot plate | Normal |
| Dysmorphology | Normal |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Normal |
| Body temperature | Normal |
| Eye morphology | Normal |
| Clinical chemistry | Normal |
| Plasma immunoglobulins | Normal |
| Haematology | Normal |
| Peripheral blood lymphocytes | Normal |
| Micronucleus test | Normal |
| Heart weight | Normal |
| Brain histopathology | Normal |
| Salmonella infection | Normal [8] |
| Citrobacter infection | Normal [9] |
| All tests and analysis from [10] [11] |
Model organisms have been used in the study of SMYD3 function. A conditional knockout mouse line, called Smyd3tm2a(KOMP)Wtsi [12] [13] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. [14] [15] [16]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. [10] [17] Twenty three tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed. [10]
SMYD3 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1 [18] and POLR2A. [18]
SMYD3 trimethylates a lysine residue on MAP3K2, which causes crosstalk into the MAP kinase signaling pathway in Ras-driven cancers. [19]
SMYD3 plays an important role in the progression of cancers in humans. It is highly over expressed in a number of cancers such as liver, breast, and colorectal carcinomas. [20] SMYD3 is known to play a role in lung, esophageal and prostate cancers also. [21]
It has been noted that in lung and colorectal cancers, MAP3K2 methylation by SMYD3 ameliorates PPA2's inhibitory control, which leads to the overriding of apoptosis signals via the activation of the MEK/ERK signalling cascade. [22] Meanwhile, in colon and liver cancers, SMYD3-mediated methylation of H3 promotes RNAP II recruitment and the associated transcription factors from proto-oncogenic regions. [21]
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.
DNA (cytosine-5)-methyltransferase 1 is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. In humans, it is encoded by the DNMT1 gene. DNMT1 forms part of the family of DNA methyltransferase enzymes, which consists primarily of DNMT1, DNMT3A, and DNMT3B.
Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein in humans that is encoded by the KDM1A gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysines 4 and 9. This enzyme can have roles critical in embryogenesis and tissue-specific differentiation, as well as oocyte growth. KDM1A was the first histone demethylase to be discovered though more than 30 have been described.
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.
Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the PRMT1 gene. The HRMT1L2 gene encodes a protein arginine methyltransferase that functions as a histone methyltransferase specific for histone H4.
Histone-lysine N-methyltransferase SUV39H1 is an enzyme that in humans is encoded by the SUV39H1 gene.
DNA (cytosine-5)-methyltransferase 3A 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.
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.
Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a, is a histone methyltransferase enzyme that in humans is encoded by the EHMT2 gene. G9a catalyzes the mono- and di-methylated states of histone H3 at lysine residue 9 and lysine residue 27.
Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the KDM4A gene.
Histone-lysine N-methyltransferase SETD7 is an enzyme that in humans is encoded by the SETD7 gene.
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. It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A, KMT2B, KMT2C, KMT2F, and KMT2G.
Lysine-specific demethylase 4C is an enzyme that in humans is encoded by the KDM4C gene.
The SET domain is a protein domain that typically has methyltransferase activity. It was originally identified as part of a larger conserved region present in the Drosophila Trithorax protein and was subsequently identified in the Drosophila Su(var)3-9 and 'Enhancer of zeste' proteins, from which the acronym SET is derived [Su(var)3-9, Enhancer-of-zeste and Trithorax].
Protein arginine methyltransferase 7 is a protein that in humans is encoded by the PRMT7 gene. Arginine methylation is an apparently irreversible protein modification catalyzed by arginine methyltransferases, such as PMT7, using S-adenosylmethionine (AdoMet) as the methyl donor. Arginine methylation is implicated in signal transduction, RNA transport, and RNA splicing.
Euchromatic histone-lysine N-methyltransferase 1, also known as G9a-like protein (GLP), is a protein that in humans is encoded by the EHMT1 gene.
SET domain containing 5 is a protein that in humans is encoded by the SETD5 gene. It is a member of the histone lysine methyltransferase family. Overexpression of SETD5 is associated positively with progression of breast cancer. Mutations in SETD5 are associated with a rare developmental disorder termed autosomal dominant mental retardation-23. MRD23 is mainly characterized by variable congenital defects and dysmorphic facies. Clinical features include developmental delay, intellectual disability, chewing abnormalities, hypospadias, and cryptorchidism in males in association with craniofacial dysmorphisms.
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.
Thomas Jenuwein is a German scientist working in the fields of epigenetics, chromatin biology, gene regulation and genome function.