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Information on EC 2.1.1.366 - [histone H3]-N6,N6-dimethyl-lysine9 N-methyltransferase and Organism(s) Mus musculus and UniProt Accession O88974
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2.1.1.366 [histone H3]-N6,N6-dimethyl-lysine9 N-methyltransferaseIUBMB Comments
The enzyme methylates only dimethylated lysine9 of histone H3 (H3K9), forming the trimethylated form. This modification influences the binding of chromatin-associated proteins. In general, the methylation of H3K9 leads to transcriptional repression of the affected target genes. The enzyme is highly upregulated in Huntington disease patients. cf. EC 2.1.1.367, [histone H3]-lysine9 N-methyltransferase, and EC 2.1.1.368, [histone H3]-lysine9 N-dimethyltransferase, and EC 2.1.1.355, [histone H3]-lysine9 N-trimethyltransferase.
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Word Map
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
kmt1e, erg-associated protein with set domain, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
KIAA0067
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KMT1E
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SETDB1
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PATHWAY SOURCE
PATHWAYS
KEGG
SYSTEMATIC NAME
IUBMB Comments
S-adenosyl-L-methionine:[histone H3]-N6,N6-dimethyl-L-lysine9 N6-methyltransferase
The enzyme methylates only dimethylated lysine9 of histone H3 (H3K9), forming the trimethylated form. This modification influences the binding of chromatin-associated proteins. In general, the methylation of H3K9 leads to transcriptional repression of the affected target genes. The enzyme is highly upregulated in Huntington disease patients. cf. EC 2.1.1.367, [histone H3]-lysine9 N-methyltransferase, and EC 2.1.1.368, [histone H3]-lysine9 N-dimethyltransferase, and EC 2.1.1.355, [histone H3]-lysine9 N-trimethyltransferase.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
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ESET can specifically methylate histone H3 while inactive toward histone H2A, H2B and H4
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
physiological function
physiological function
bivalend combinantion, dually marked histones H3K9me3/H3K14ac modification in the liver, is significantly decreased in old hepatocytes. A correlation between H3K9me3/H3K14ac bulk bivalent genomic regions and dually marked single nucleosomes is suggested. Histone H3K9 deacetylase Hdac3, as well as H3K9 methyltransferase Setdb1, found in complex Kap1, occupy both bulk and single nucleosome bivalent regions in both young and old livers, correlating to presence of H3K9me3. Expression of genes associated with bivalent regions in young liver, including those regulating cholesterol secretion and triglyceride synthesis, is upregulated in old liver once the bivalency is lost
physiological function
deletion of the catalytic domain of either histone methyltransferases EHMT2 or SETDB1 in growing oocytes leads to significant reduction of global H3K9me2 or H3K9me3 levels, respectively, in the maternal pronucleus. The asymmetry of global 5-methylcytosine (5mC) oxidation is significantly reduced in the zygotes that carry maternal mutation of either the Ehmt2 or Setdb1 genes. The levels of 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine increase, and 5mC levels decrease in the mutant maternal pronuclei. H3K9me3-rich rings around the nucleolar-like bodies retain 5mC in the maternal mutant zygotes. The maternal pronuclei expand in size in the mutant zygotes and contain a significantly increased number of nucleolar-like bodies compared with normal zygotes
physiological function
Setdb1 has a constant role in endogenous retrovirus silencing. Distinctive sets of endogenous retroviruses are reactivated in different types of Setdb1-deficient somatic cells, including the VL30-class of endogenous retroviruses in mouse embryonic fibroblasts. A viral defense response is induced in immortalized Setdb1 knock-out embryonic fibroblasts
physiological function
Setdb1 in macrophages potently suppresses Toll-like receptor TLR4-mediated expression of proinflammatory cytokines including interleukin-6 through its methyltransferase activity. Setdb1-deficiency decreases the basal H3K9 methylation levels and augments TLR4-mediated NF-kappaB recruitment on the proximal promoter region of interleukin-6, thereby accelerating interleukin-6 promoter activity. Macrophage-specific Setdb1-knockout mice exhibit higher serum interleukin-6 concentrations in response to lipopolysaccharide challenge and are more susceptible to endotoxin shock than wild-type mice
physiological function
SETDB1 is an epigenetic regulator of primordial germ cell fate determination. SETDB1-deficient embryos exhibit drastic reduction of nascent primordial germ cells. Dppa2, Otx2 and Utf1 are derepressed whereas mesoderm development-related genes, including BMP4 signaling-related genes, are downregulated by SETDB1 knockdown during primordial germ cell-like cell induction. Binding of SETDB1 is observed at the flanking regions of Dppa2, Otx2 and Utf1 in cell aggregates containing primordial germ cell-like cell induction, and trimethylation of lysine 9 of histone H3 is reduced by SETDB1 knockdown at those regions
physiological function
SETDB1 is the bridge linking the DNA damage response to meiotic silencing in male mice. At the onset of silencing, X chromosome H3K9 trimethylation enrichment is downstream of DNA damage response factors. Without SETDB1, the X chromosome accrues DNA damage response proteins but not H3K9me3, so sex chromosome remodeling and silencing fail, causing germ cell apoptosis. Setdb1 deletion causes midpachytene apoptosis. SETDB1 is required for epigenetic remodeling of the XY pair, for condensation of the XY pair and for XY silencing at pachynema
physiological function
SETDB1 regulates the PTEN/AKT/FOXO1 pathway to inhibit spermatogonial stem cell apoptosis. SETDB1 interacts and coordinates with AKT to regulate FOXO1 activity and expression of the downstream target genes Bim and Puma. Among the SETDB1-bound genes, the H3K9me3 levels on the promoter regions of Bim and Pten decrease in the SETDB1-knock down group. The H3K9me3 status on promoters of Bax and Puma remains unchanged
physiological function
the SETDB1 repressor complex, which involves multiple KRAB zinc finger proteins, shields neuronal genomes from excess CTCF binding and is critically required for structural maintenance of cPcdh topologically associated domain. Neuronal ablation of Setdb1 leads to locus-specific disintegration of megabase-scale chromosomal conformations. The cPcdh topologically associated domain in neurons from mutant mice shows abnormal accumulation of the transcriptional regulator and three-dimensional genome organizer CTCF at cryptic binding sites, in conjunction with DNA cytosine hypomethylation, histone hyperacetylation and upregulated expression. Genes encoding stochastically expressed protocadherins are transcribed by increased numbers of cortical neurons. SETDB1-dependent loop formations bypass 0.2-1 Mb of linear genome and radiate from the cPcdh topologically associated domain fringes toward cis-regulatory sequences within the cPcdh locus
physiological function
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deletion of Setdb1 in Meckel's cartilage tissue leads to its enlargement. Chondrocytes from the Meckel's cartilage of Setdb1 conditional KO mice show increased size. At embryonic days 16.5 and 18.5, part of the perichondrium is disrupted and mineralization is observed in the Meckel's cartilage. Inhibition of Setdb1 causes increased proliferation in chondrocytes in the Meckel's cartilage as well as in siRNA-treated ATDC5 cells. Decreased expression of chondrogenic genes, such as Sox9, Mmp13, Collagen II, and Aggrecan, is observed as a result of Setdb1 inhibition in ATDC5 cells. SMAD-dependent BMP signaling is significantly increased by the loss of Setdb1 in both the Meckel's cartilage of Setdb1 conditional KO mice and siRNA-treated ATDC5 cells
physiological function
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H3K9 methylation reader M-phase phosphoprotein 8 (MPP8) interacts physically and functionally with SETDB1 in embryonic stem cells. MPP8 and SETDB1 coregulate a significant number of common genomic targets, especially the DNA satellite repeats
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SETB1_MOUSE
1307
0
144549
Swiss-Prot
other Location (Reliability: 5)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
x * 145000, calculated from sequence, x * 180000, SDS-PAGE of recombinant protein
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C1242T
highly conserved cysteine residues, mutant has lost histone methyltransferase activity
C798L
highly conserved cysteine residues, mutant has lost histone methyltransferase activity
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
loss of SETDB1 from pancreas accelerates formation of premalignant lesions in mice with pancreata that express activated KRAS. Expression of genes in the apoptotic pathway is upregulated and genes are regulated by p53 in SETDB1-deficient pancreata. Deletion of Setdb1 from pancreas prevents formation of pancreatic ductal adenocarcinoma, concomitant with increased apoptosis and upregulated expression of Trp53 in mice heterozygous for disruption of Trp53. Pancreata of mice with homozygous disruption of Trp53 have no increased apoptosis, and pancreatic ductal adenocarcinomas develop. SETDB1 binds to the Trp53 promoter to regulate its expression
medicine
overexpression of SETDB1 contributes to melanoma tumorigenesis. SETDB1 is highly amplified in melanoma cells. Increased expression of SETDB1 correlates with SETDB1 amplification and is associated with a more aggressive phenotype in in vitro and in vivo studies. SETDB1 implements its effects via regulation of thrombospondin 1, and the SET-domain of SETDB1 is essential for the maintenance of its tumorigenic activity. Inhibition of SETDB1 reduces cell growth in melanomas resistant to targeted treatments
medicine
Setdb1 has a constant role in endogenous retrovirus silencing. Distinctive sets of endogenous retroviruses are reactivated in different types of Setdb1-deficient somatic cells, including the VL30-class of endogenous retroviruses in mouse embryonic fibroblasts. A viral defense response is induced in immortalized Setdb1 knock-out embryonic fibroblasts
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hachiya, R.; Shiihashi, T.; Shirakawa, I.; Iwasaki, Y.; Matsumura, Y.; Oishi, Y.; Nakayama, Y.; Miyamoto, Y.; Manabe, I.; Ochi, K.; Tanaka, M.; Goda, N.; Sakai, J.; Suganami, T.; Ogawa, Y.
The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages
Sci. Rep.
6
28845
2016
Mus musculus (O88974)
Yang, L.; Xia, L.; Wu, D.Y.; Wang, H.; Chansky, H.A.; Schubach, W.H.; Hickstein, D.D.; Zhang, Y.
Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor
Oncogene
21
148-152
2002
Mus musculus (O88974)
Price, A.J.; Manjegowda, M.C.; Kain, J.; Anandh, S.; Bochkis, I.M.
Hdac3, Setdb1, and Kap1 mark H3K9me3/H3K14ac bivalent regions in young and aged liver
Aging Cell
19
e13092
2020
Mus musculus (O88974)
Yahiro, K.; Higashihori, N.; Moriyama, K.
Histone methyltransferase Setdb1 is indispensable for Meckels cartilage development
Biochem. Biophys. Res. Commun.
482
883-888
2017
Mus musculus
Liu, T.; Chen, X.; Li, T.; Li, X.; Lyu, Y.; Fan, X.; Zhang, P.; Zeng, W.
Histone methyltransferase SETDB1 maintains survival of mouse spermatogonial stem/progenitor cells via PTEN/AKT/FOXO1 pathway
Biochim. Biophys. Acta
1860
1094-1102
2017
Mus musculus (O88974)
Hirota, T.; Blakeley, P.; Sangrithi, M.N.; Mahadevaiah, S.K.; Encheva, V.; Snijders, A.P.; ElInati, E.; Ojarikre, O.A.; de Rooij, D.G.; Niakan, K.K.; Turner, J.M.A.
SETDB1 links the meiotic DNA damage response to sex chromosome silencing in mice
Dev. Cell
47
645-659.e6
2018
Mus musculus (O88974)
Mochizuki, K.; Tando, Y.; Sekinaka, T.; Otsuka, K.; Hayashi, Y.; Kobayashi, H.; Kamio, A.; Ito-Matsuoka, Y.; Takehara, A.; Kono, T.; Osumi, N.; Matsui, Y.
SETDB1 is essential for mouse primordial germ cell fate determination by ensuring BMP signaling
Development
145
dev164160
2018
Mus musculus (O88974)
Ogawa, S.; Fukuda, A.; Matsumoto, Y.; Hanyu, Y.; Sono, M.; Fukunaga, Y.; Masuda, T.; Araki, O.; Nagao, M.; Yoshikawa, T.; Goto, N.; Hiramatsu, Y.; Tsuda, M.; Maruno, T.; Nakanishi, Y.; Hussein, M.S.; Tsuruyama, T.; Takaori, K.; Uemoto, S.; Seno, H.
SETDB1 inhibits p53-mediated apoptosis and is required for formation of pancreatic ductal adenocarcinomas in mice
Gastroenterology
159
682-696.e13
2020
Homo sapiens (Q15047), Mus musculus (O88974)
Cruz-Tapias, P.; Robin, P.; Pontis, J.; Del Maestro, L.; Ait-Si-Ali, S.
The H3K9 methylation writer SETDB1 and its reader MPP8 cooperate to silence satellite DNA repeats in mouse embryonic stem cells
Genes (Basel)
10
750
2019
Mus musculus
Orouji, E.; Federico, A.; Larribere, L.; Novak, D.; Lipka, D.B.; Assenov, Y.; Sachindra, S.; Hueser, L.; Granados, K.; Gebhardt, C.; Plass, C.; Umansky, V.; Utikal, J.
Histone methyltransferase SETDB1 contributes to melanoma tumorigenesis and serves as a new potential therapeutic target
Int. J. Cancer
145
3462-3477
2019
Mus musculus (O88974), Homo sapiens (Q15047)
Kato, M.; Takemoto, K.; Shinkai, Y.
A somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing
Nat. Commun.
9
1683
2018
Mus musculus (O88974)
Jiang, Y.; Loh, Y.E.; Rajarajan, P.; Hirayama, T.; Liao, W.; Kassim, B.S.; Javidfar, B.; Hartley, B.J.; Kleofas, L.; Park, R.B.; Labonte, B.; Ho, S.M.; Chandrasekaran, S.; Do, C.; Ramirez, B.R.; Peter, C.J.; C W, J.T.; Safaie, B.M.; Morishita, H.; Roussos, P.; Nestler, E.J.; Schaefer, A.; Tycko, B.; Brennand, K.
The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain
Nat. Genet.
49
1239-1250
2017
Mus musculus (O88974)
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