SETDB1

Histone-lysine N-methyltransferase SETDB1 is an enzyme that in humans is encoded by the SETDB1 gene.[5][6] SETDB1 is also known as KMT1E or H3K9 methyltransferase ESET.

SETDB1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3DLM, 4X3S, 5KE2
Identifiers
Aliases	SETDB1, ESET, H3-K9-HMTase4, KG1T, KMT1E, TDRD21, SET domain bifurcated 1, SET domain bifurcated histone lysine methyltransferase 1
External IDs	OMIM: 604396 MGI: 1934229 HomoloGene: 32157 GeneCards: SETDB1
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q21.3 Start 150,926,263 bp[1] End 150,964,744 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 F2.1 Start 95,323,525 bp[2] End 95,357,202 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • methyltransferase activity • transferase activity • DNA binding • promoter-specific chromatin binding • zinc ion binding • histone-lysine N-methyltransferase activity • metal ion binding • GO:0001948 protein binding • chromatin binding • histone methyltransferase activity (H3-K9 specific) Cellular component • intracellular membrane-bounded organelle • cell membrane • nucleoplasm • chromosome • cell nucleus • cytosol • cytoplasm Biological process • regulation of transcription, DNA-templated • positive regulation of methylation-dependent chromatin silencing • response to vitamin • transcription, DNA-templated • methylation • histone lysine methylation • Ras protein signal transduction • response to ethanol • chromatin organization • negative regulation of single stranded viral RNA replication via double stranded DNA intermediate • histone H3-K9 methylation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9869	84505
Ensembl	ENSG00000143379	ENSMUSG00000015697
UniProt	Q15047	O88974
RefSeq (mRNA)	NM_001145415 NM_001243491 NM_012432 NM_001366417 NM_001366418	NM_001163641 NM_001163642 NM_018877
RefSeq (protein)	NP_001138887 NP_001230420 NP_036564 NP_001353346 NP_001353347	n/a
Location (UCSC)	Chr 1: 150.93 – 150.96 Mb	Chr 3: 95.32 – 95.36 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

The SET domain is a highly conserved, approximately 150-amino acid motif implicated in the modulation of chromatin structure. 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. Studies have suggested that the SET domain may be a signature of proteins that modulate transcriptionally active or repressed chromatin states through chromatin remodeling activities.[6]

Model organisms

Setdb1 knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Abnormal
Recessive lethal study	Abnormal
Homozygous Fertility	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
Haematology	Normal
Peripheral blood lymphocytes	Abnormal[7]
Micronucleus test	Normal
Heart weight	Normal
Tail epidermis wholemount	Normal
Skin Histopathology	Normal
Brain histopathology	Normal
MicroCT & Quantitative Faxitron	Abnormal
Salmonella infection	Normal[8]
Citrobacter infection	Normal[9]
All tests and analysis from[10][11]

Model organisms have been used in the study of SETDB1 function. A conditional knockout mouse line, called Setdb1^{tm1a(EUCOMM)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.[14][15][16]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[10][17] Twenty seven tests were carried out on mutant mice and four significant abnormalities were observed.[10] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and two significant abnormalities were observed. Females had abnormal peripheral blood lymphocytes data and both sexes displayed increased bone strength and mineral content.[10]

Zebrafish are an important model organism to study developmental biology and have been used to study cancer genetics. A screen to identify new oncogenes in melanoma performed in zebrafish identified SETDB1 as an oncogene that cooperates with another cancer gene, BRAF, to accelerate melanoma onset.[18] Subsequent reports have linked SETDB1 to hepatocellular carcinoma [19]

Interactions

SETDB1 has been shown to interact with TRIM28.[20]>

References

1. GRCh38: Ensembl release 89: ENSG00000143379 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000015697 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Harte PJ, Wu W, Carrasquillo MM, Matera AG (June 1999). "Assignment of a novel bifurcated SET domain gene, SETDB1, to human chromosome band 1q21 by in situ hybridization and radiation hybrids". Cytogenet. Cell Genet. 84 (1–2): 83–6. doi:10.1159/000015220. PMID 10343109.
6. "Entrez Gene: SETDB1 SET domain, bifurcated 1".
7. "Peripheral blood lymphocytes data for Setdb1". Wellcome Trust Sanger Institute.
8. "Salmonella infection data for Setdb1". Wellcome Trust Sanger Institute.
9. "Citrobacter infection data for Setdb1". Wellcome Trust Sanger Institute.
10. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
11. Mouse Resources Portal, Wellcome Trust Sanger Institute.
12. "International Knockout Mouse Consortium".
13. "Mouse Genome Informatics".
14. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
15. Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
16. Collins FS, Rossant J, Wurst W (2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
17. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
18. Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V, Fritsch L, Lin WM, Hollmann TJ, Ferré F, Bourque C, Burke CJ, Turner L, Uong A, Johnson LA, Beroukhim R, Mermel CH, Loda M, Ait-Si-Ali S, Garraway LA, Young RA, Zon LI (March 2011). "The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset". Nature. 471 (7339): 513–7. doi:10.1038/nature09806. PMC 3348545. PMID 21430779.
19. Fei Q, Shang K, Zhang J, Chuai S, Kong D, Zhou T, Fu S, Liang Y, Li C, Chen Z, Zhao Y, Yu Z, Huang Z, Hu M, Ying H, Chen Z, Zhang Y, Xing F, Zhu J, Xu H, Zhao K, Lu C, Atadja P, Xiao ZX, Li E, Shou J (October 2015). "Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53". Nat Commun. 6: 8651. doi:10.1038/ncomms9651. PMC 5426523. PMID 26471002.
20. Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ (April 2002). "SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins". Genes Dev. 16 (8): 919–32. doi:10.1101/gad.973302. PMC 152359. PMID 11959841.

Further reading

• Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S (1994). "Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1". DNA Res. 1 (5): 223–9. doi:10.1093/dnares/1.5.223. PMID 7584044.
• Yang L, Xia L, Wu DY, Wang H, Chansky HA, Schubach WH, Hickstein DD, Zhang Y (2002). "Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor". Oncogene. 21 (1): 148–52. doi:10.1038/sj.onc.1204998. PMID 11791185.
• Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ (2002). "SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins". Genes Dev. 16 (8): 919–32. doi:10.1101/gad.973302. PMC 152359. PMID 11959841.
• Yang L, Mei Q, Zielinska-Kwiatkowska A, Matsui Y, Blackburn ML, Benedetti D, Krumm AA, Taborsky GJ, Chansky HA (2003). "An ERG (ets-related gene)-associated histone methyltransferase interacts with histone deacetylases 1/2 and transcription co-repressors mSin3A/B". Biochem. J. 369 (Pt 3): 651–7. doi:10.1042/BJ20020854. PMC 1223118. PMID 12398767.
• Nakayama M, Kikuno R, Ohara O (2002). "Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs". Genome Res. 12 (11): 1773–84. doi:10.1101/gr.406902. PMC 187542. PMID 12421765.
• Ayyanathan K, Lechner MS, Bell P, Maul GG, Schultz DC, Yamada Y, Tanaka K, Torigoe K, Rauscher FJ (2003). "Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation". Genes Dev. 17 (15): 1855–69. doi:10.1101/gad.1102803. PMC 196232. PMID 12869583.
• Wang H, An W, Cao R, Xia L, Erdjument-Bromage H, Chatton B, Tempst P, Roeder RG, Zhang Y (2003). "mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression". Mol. Cell. 12 (2): 475–87. doi:10.1016/j.molcel.2003.08.007. PMID 14536086.
• Paces-Fessy M, Boucher D, Petit E, Paute-Briand S, Blanchet-Tournier MF (2004). "The negative regulator of Gli, Suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins". Biochem. J. 378 (Pt 2): 353–62. doi:10.1042/BJ20030786. PMC 1223961. PMID 14611647.
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM (2004). "Functional proteomics mapping of a human signaling pathway". Genome Res. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
• Sarraf SA, Stancheva I (2004). "Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly". Mol. Cell. 15 (4): 595–605. doi:10.1016/j.molcel.2004.06.043. PMID 15327775.
• Goehler H, Lalowski M, Stelzl U, Waelter S, Stroedicke M, Worm U, Droege A, Lindenberg KS, Knoblich M, Haenig C, Herbst M, Suopanki J, Scherzinger E, Abraham C, Bauer B, Hasenbank R, Fritzsche A, Ludewig AH, Büssow K, Buessow K, Coleman SH, Gutekunst CA, Landwehrmeyer BG, Lehrach H, Wanker EE (2004). "A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease". Mol. Cell. 15 (6): 853–65. doi:10.1016/j.molcel.2004.09.016. PMID 15383276.
• Ichimura T, Watanabe S, Sakamoto Y, Aoto T, Fujita N, Nakao M (2005). "Transcriptional repression and heterochromatin formation by MBD1 and MCAF/AM family proteins". J. Biol. Chem. 280 (14): 13928–35. doi:10.1074/jbc.M413654200. PMID 15691849.
• Verschure PJ, van der Kraan I, de Leeuw W, van der Vlag J, Carpenter AE, Belmont AS, van Driel R (2005). "In vivo HP1 targeting causes large-scale chromatin condensation and enhanced histone lysine methylation". Mol. Cell. Biol. 25 (11): 4552–64. doi:10.1128/MCB.25.11.4552-4564.2005. PMC 1140641. PMID 15899859.
• Gevaert K, Staes A, Van Damme J, De Groot S, Hugelier K, Demol H, Martens L, Goethals M, Vandekerckhove J (2005). "Global phosphoproteome analysis on human HepG2 hepatocytes using reversed-phase diagonal LC". Proteomics. 5 (14): 3589–99. doi:10.1002/pmic.200401217. PMID 16097034.
• Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–68. doi:10.1016/j.cell.2005.08.029. hdl:11858/00-001M-0000-0010-8592-0. PMID 16169070.
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
• Orouji E, Federico A, Larribere L, Novak D, Lipka DB, Assenov Y, Sachindra S, Hueser L, Granados K, Gebhardt C, Plass C, Umansky V, Utikal J (2019). "Histone methyltransferase SETDB1 contributes to melanoma tumorigenesis and serves as a new potential therapeutic target". Int J Cancer. 0 (12): 3462–3477. doi:10.1002/ijc.32432. PMID 31131878.

External links

• FactorBook SETDB1
• Overview of all the structural information available in the PDB for UniProt: Q15047 (Histone-lysine N-methyltransferase SETDB1) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.