SETDB1

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; OMA:SETDB1 - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1q21.3 Start 150,926,263 bp End 150,964,744 bp
Gene location (Mouse) Chr. Chromosome 3 (mouse) Band 3|3 F2.1 Start 95,230,836 bp End 95,264,513 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sural nerve monocyte granulocyte right lobe of thyroid gland right ovary left ovary left testis right testis right uterine tube left lobe of thyroid gland Top expressed in secondary oocyte zygote primary oocyte Ileal epithelium tail of embryo otic placode genital tubercle superior surface of tongue gallbladder ventricular zone More reference expression data BioGPS 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 protein binding chromatin binding histone methyltransferase activity (H3-K9 specific) Cellular component intracellular membrane-bounded organelle plasma membrane nucleoplasm chromosome nucleus cytosol cytoplasm Biological process regulation of transcription, DNA-templated positive regulation of DNA methylation-dependent heterochromatin assembly 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: 95.23 – 95.26 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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.

Function

The human SETDB1 protein consists of multiple N-terminal and C-terminal functional domains linked by an intervening sequence of variable length, which can exist in multiple isoforms generated by alternative splicing.

The chief functional domain is the SET domain, a highly conserved, approximately 150-amino acid motif positioned near SETDB1's C-terminus and 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. In SETDB1, the SET domain is bifurcated into two non-contiguous subdomains.

The SET domain functions as an H3K9-specific methyltransferase which exclusively methylates histone H3 lysine 9 (H3K9) by catalyzing the covalent attachment of a methyl group (—CH
₃) to this particular lysine's electrophilic side chain. It is capable of adding to unmethylated H3K9 to convert it to the monomethylated state (H3K9me1), but its primary substrates are the mono- and dimethylated forms, which it converts to dimethylated (H3K9me2) and trimethylated (H3K9me3) states, respectively. H3K9 methylation is a classic epigenetic mark that recruits heterochromatin protein 1 (HP1) to the marked nucleosome, which then induces the condensation of the nucleosome into repressive heterochromatin, making nearby DNA sequences less accessible to transcriptional machinery and hence downregulating the expression of nearby genes. Thus SETDB1 is a core functional enzyme in repressive pathways that control gene expression by the post-translational modification of H3K9. A specific residue within the SET domain, lysine 867 (K867), is monoubiquitinated by the protein ATF7IP. This modification helps retain SETDB1 in the nucleus, prevents its degradation by proteasomes, and is necessary for SETDB1 to have methyltransferase activity.

In the N-terminal region, the SETDB1 protein also contains a methyl CpG-binding domain (MBD) capable of recognizing CpG-rich genomic DNA and interacting with DNA methyltransferases. Two consecutive Tudor domains help target SETDB1 specifically to H3K9 by functioning as anchors to either side of the K9 residue in the N-terminal tail of histone H3.

Interactions

In mammals, SETDB1 has been shown to interact with the mediator protein TRIM28 and various DNA-binding KRAB domain-containing transcription factors, forming a protein complex that is responsible for much of the repressive modification of H3K9 throughout the genome. TRIM28 effectively links SETDB1's methyltransferase activity to the KRAB domain's ability to bind DNA at specific sequences, allowing the selective modification of H3K9 at sequence-specific loci.

During meiosis, synapsis of homologous chromosomes ensures correct homologous chromosome segregation. Asynapsed homologs are transcriptionally inactivated by a process of meiotic silencing. Meiotic silencing depends on the DNA damage response network. SETDB1 has been identified as the bridge linking the DNA damage response to chromosome silencing in male mice.

See also

• SETD1A, a protein that is highly homologous to SETDB1

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. S2CID 10912876.
• 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.
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• 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. S2CID 895879.
• 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. S2CID 8235923.
• 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. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
• 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. 145 (12): 3462–3477. doi:10.1002/ijc.32432. PMID 31131878.
• Strepkos D, Markouli M, Klonou A, Papavassiliou AG, Piperi C (2021). "Histone methyltransferase SETDB1: A common denominator of tumorigenesis with therapeutic potential". Cancer Research. 81 (3): 525–534. doi:10.1158/0008-5472.CAN-20-2906. PMID 33115801. S2CID 226046421.
• Cao N, Yu Y, Zhu H, Chen M, Chen P, Zhuo M, Ye M (2020). "SETDB1 promotes the progression of colorectal cancer via epigenetically silencing p21 expression". Cell Death & Disease. 11 (5) 351. doi:10.1038/s41419-020-2561-6. PMC 7214465. PMID 32393761.
• Lee S, Lee C, Hwang CY, Kim D, Han Y, Hong SN, Cho KH (2020). "Network inference analysis identifies SETDB1 as a key regulator for reverting colorectal cancer cells into differentiated normal-like cells". Molecular Cancer Research. 18 (1): 118–129. doi:10.1158/1541-7786.MCR-19-0450. PMID 31896605.
• Fukuda K, Shinkai Y (2020). "SETDB1-Mediated silencing of retroelements". Viruses. 12 (6): 596. doi:10.3390/v12060596. PMC 7354471. PMID 32486217.

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.