SETDB1

Summary

SETDB1 (SET domain bifurcated histone lysine methyltransferase 1, HGNC:10761) is a protein-coding gene on chromosome 1q21.3, encoding Histone-lysine N-methyltransferase SETDB1 (Q15047). Histone methyltransferase that specifically trimethylates ‘Lys-9’ of histone H3 (H3K9me3). It is a selective cancer dependency (DepMap: 50.1% of cell lines).

This gene encodes a histone methyltransferase which regulates histone methylation, gene silencing, and transcriptional repression. This gene has been identified as a target for treatment in Huntington Disease, given that gene silencing and transcription dysfunction likely play a role in the disease pathogenesis. Alternatively spliced transcript variants of this gene have been described.

Source: NCBI Gene 9869 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 107 total
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 8 cancer types
• Cancer dependency (DepMap): dependent in 50.1% of screened cell lines
• MANE Select transcript: NM_001366418

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10761
Approved symbol	SETDB1
Name	SET domain bifurcated histone lysine methyltransferase 1
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	KG1T, KIAA0067, ESET, KMT1E, TDRD21
Ensembl gene	ENSG00000143379
Ensembl biotype	protein_coding
OMIM	604396
Entrez	9869

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 18 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000271640, ENST00000368962, ENST00000368963, ENST00000368964, ENST00000368969, ENST00000423081, ENST00000448029, ENST00000459773, ENST00000463774, ENST00000481219, ENST00000487584, ENST00000497314, ENST00000498193, ENST00000525956, ENST00000528749, ENST00000533529, ENST00000534805, ENST00000690229, ENST00000692314, ENST00000692827, ENST00000884739, ENST00000884740, ENST00000884741, ENST00000884742, ENST00000884743, ENST00000923174, ENST00000923175

RefSeq mRNA: 14 — MANE Select: NM_001366418 NM_001145415, NM_001243491, NM_001366417, NM_001366418, NM_001393958, NM_001393959, NM_001393960, NM_001393961, NM_001393964, NM_001393965, NM_001393966, NM_001393967, NM_001393968, NM_012432

CCDS: CCDS44217, CCDS58026, CCDS91050, CCDS91051, CCDS972

Canonical transcript exons

ENST00000692827 — 22 exons

Exon	Start	End
ENSE00001618975	150951365	150951481
ENSE00001620114	150944918	150945108
ENSE00001635483	150960563	150961191
ENSE00001653763	150963530	150963741
ENSE00001660078	150942563	150942688
ENSE00001664903	150946886	150947012
ENSE00001670531	150942852	150943053
ENSE00001681883	150941329	150941428
ENSE00001686493	150959178	150959347
ENSE00001700401	150949122	150949278
ENSE00001759825	150962130	150962158
ENSE00001791352	150950458	150951090
ENSE00001927134	150949367	150949525
ENSE00003509425	150939940	150939974
ENSE00003523534	150929967	150930118
ENSE00003524194	150927704	150927974
ENSE00003569294	150963995	150964083
ENSE00003570414	150962974	150963139
ENSE00003615098	150962587	150962719
ENSE00003691683	150943920	150943993
ENSE00003923426	150964247	150964737
ENSE00003924041	150926363	150926517

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 94.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.3690 / max 380.6294, expressed in 1812 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5161	20.1028	1812
5160	0.8640	528
5159	0.3979	205
5163	0.0043	2

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	94.34	gold quality
monocyte	CL:0000576	93.90	gold quality
mononuclear cell	CL:0000842	93.61	gold quality
leukocyte	CL:0000738	93.39	gold quality
granulocyte	CL:0000094	93.37	gold quality
right lobe of thyroid gland	UBERON:0001119	92.68	gold quality
right ovary	UBERON:0002118	92.33	gold quality
left ovary	UBERON:0002119	92.32	gold quality
left testis	UBERON:0004533	92.29	gold quality
right testis	UBERON:0004534	92.29	gold quality
right uterine tube	UBERON:0001302	92.21	gold quality
left lobe of thyroid gland	UBERON:0001120	92.19	gold quality
body of uterus	UBERON:0009853	91.97	gold quality
spleen	UBERON:0002106	91.72	gold quality
mucosa of stomach	UBERON:0001199	91.64	gold quality
tibial nerve	UBERON:0001323	91.55	gold quality
thyroid gland	UBERON:0002046	91.53	gold quality
ganglionic eminence	UBERON:0004023	91.52	gold quality
cortical plate	UBERON:0005343	91.51	gold quality
adrenal tissue	UBERON:0018303	91.36	gold quality
body of pancreas	UBERON:0001150	91.34	gold quality
metanephros cortex	UBERON:0010533	91.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.11	gold quality
endocervix	UBERON:0000458	91.07	gold quality
left uterine tube	UBERON:0001303	90.90	gold quality
testis	UBERON:0000473	90.76	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.72	gold quality
ectocervix	UBERON:0012249	90.60	gold quality
upper lobe of left lung	UBERON:0008952	90.58	gold quality
skin of leg	UBERON:0001511	90.45	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREBBP, DNMT3A, ETS2, EZH2, JARID2, MBD1, PAX3, SP1, SP3, SPI1, TP53

miRNA regulators (miRDB)

40 targeting SETDB1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-6871-3P	99.43	68.85	741
HSA-MIR-3614-5P	99.30	65.25	837
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4263	99.18	69.25	2236
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-3130-5P	98.14	66.00	711
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-1279	97.83	67.50	1898
HSA-MIR-1972	97.67	67.38	1172

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 50.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins; KAP-1, SETDB1, H3-MeK9, and HP1 are enriched at promoter sequences of a euchromatic gene silenced by the KRAB-KAP-1 repression system (PMID:11959841)
• mAM/hAM facilitates conversion of H3-K9 dimethyl to trimethyl by ESET/SETDB1 (PMID:14536086)
• These data suggest that MBD1.MCAF1.SETDB1 complex facilitates the formation of heterochromatic domains, emphasizing the role of MCAF/AM family proteins in epigenetic control, and describe a new family member, MCAF2 (ATF7IP2). (PMID:15691849)
• histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells (PMID:16682412)
• modulation of gene silencing mechanisms, through regulation of the ESET gene is important to neuronal survival and, as such, may be a promising treatment in Huntington’s disease patients (PMID:17142323)
• Akt/PKB interacts with the histone H3 methyltransferase SETDB1 and coordinates to silence gene expression. (PMID:17577629)
• SETDB1 can specifically methylate HIV-1 Tat preferentially at lysine 51. (PMID:18498648)
• analysis of a KRAB domain-containing ZNF (ZNF274) that is involved in recruitment of the KAP1 and SETDB1 to specific regions of the human genome (PMID:21170338)
• studies establish SETDB1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis (PMID:21430779)
• A transgenic Setdb1 model established a link between this gene and behavior. (PMID:23055267)
• SETDB1 is a bona fide oncogene undergoing gene amplification-associated activation in lung cancer. (PMID:23770855)
• SETDB1 expression was upregulated in glioma cell lines and in glioma tissues compared to normal brain, being positively correlated with grade and histological malignancy. (PMID:23943221)
• of ESET plays an essential role in the maintenance of articular cartilage by preventing articular chondrocytes from terminal differentiation and may have implications in joint diseases such as osteoarthritis. (PMID:24056368)
• data suggested that SETDB1 is overexpressed in human PCa. Silencing SETDB1 inhibited PCa cell proliferation, migration and invasion (PMID:24556744)
• overexpression of SETDB1 or LSD1 had no prognostic impact in patients with melanoma (PMID:24658378)
• SETDB1 is associated with frequent methylation of the euchromatic p16(INK) (4A) promoter and several prognostic parameters in melanomas (PMID:24673285)
• This observation suggests that the ZNF274/SETDB1 complex bound to the SNORD116 cluster may protect the Prader-Willi syndrome induced pluripotent cells from DNA demethylation during early development. (PMID:24760766)
• MiR-7, inhibited indirectly by lincRNA HOTAIR, directly inhibits SETDB1 and reverses the Epithelial-mesenchymal transition of breast cancer stem cells by down regulating the STAT3 pathway (PMID:25070049)
• Report elevated levels of SETDB1 in non-small lung cancers, associated with neoplasm grading and tumor growth. (PMID:25404354)
• Together, our findings defined an essential role for the KMT1E/SMAD2/3 repressor complex in TGFbeta-mediated lung cancer metastasis. (PMID:25477335)
• Authors demonstrate that a KMT1E-containing complex directly interacts with the FcgammaRIIb promoter and that histone H3 at lysine 9 tri-methylation at this promoter is dependent on Setdb1 (PMID:25569264)
• Exogenous expression of MyoD reversed transcriptional repression of MyoD promoter-driven lucif-erase reporter by Setdb1 shRNA and rescued myogenic differentiation of C2C12 myoblast cells depleted of endogenous Setdb1. (PMID:25715926)
• Upon HBV infection, cellular mechanisms involving SETDB1-mediated H3K9me3 and HP1 induce silencing of HBV cccDNA transcription through modulation of chromatin structure. (PMID:26143443)
• SETDB1, localized in the nucleus, might undergo degradation by the proteasome and be exported to the cytosol, resulting in its detection mainly in the cytosol. (PMID:26296461)
• regulates cancer cell growth via methylation of p53 (PMID:26471002)
• SETDB1 is an oncogene that is frequently up-regulated in human HCCs; the multiplicity of SETDB1 activating mechanisms at the chromosomal, transcriptional, and posttranscriptional levels together facilitates SETDB1 up-regulation in human HCC (PMID:26481868)
• BRCA1 and SETDB1 stand out as the most significant prognostic markers in this group of patients (PMID:26542178)
• results indicate that ATF7IP does not directly modulate SETDB1 catalytic activity, suggesting alternate roles, such as affecting cellular localization or mediating interaction with additional binding partners. (PMID:26813693)
• SETDB1 mutations are associated with malignant pleural mesotheliomas. (PMID:26824986)
• We identified a list of thirty genes repressed by DeltaNp63 in a SETDB1-dependent manner, whose expression is positively correlated to survival of breast cancer patients. These results suggest that p63 and SETDB1 expression, together with the repressed genes, may have diagnostic and prognostic potential (PMID:26840455)
• The SETDB1 protein was closely associated with the prognosis of prostate cancer (PCa). Bioinformatics suggested that SETDB1 might promote PCa bone metastasis through the WNT pathway. In conclusion, SETDB1 might be associated with the development of bone metastases from PCa (PMID:26846621)
• These results suggest that SETDB1- mediated FosB expression is a common molecular phenomenon, and might be a novel pathway responsible for the increase in cell proliferation that frequently occurs during anticancer drug therapy. (PMID:26949019)
• analysis of a 1q21.3 deletion encompassing SETDB1 that provides further support for the role of chromatin modifiers in the etiology of autism spectrum disorder (PMID:27119313)
• Authors observed several complementary mechanisms contributing to the upregulation of SETDB1 in HCC cells. Besides copy number gains at the SETDB1 gene locus at chromosome 1q21 enhanced SETDB1 transcription mediated by the transcription factor SP1 could be detected. (PMID:27164857)
• SETDB1, a major histone H3K9 methyltransferase is monoubiquitinated at the evolutionarily conserved lysine-867 in its SET-Insertion domain. This ubiquitination is directly catalyzed by UBE2E family of E2 enzymes in an E3-independent manner while the conjugated-ubiquitin (Ub) is protected from active deubiquitination. (PMID:27237050)
• these data identify a critical functional role for ATF7IP in heterochromatin formation by regulating SETDB1 abundance in the nucleus. (PMID:27732843)
• These results suggest that the ubiquitination of SETDB1 at lysine 867 controls the expression of its target gene by activating its H3K9 methyltransferase activity. (PMID:27798683)
• SETDB1 triggers silencing of retrotransposons to inhibit the interferon response in acute myeloid leukemia cells. (PMID:28887438)
• SETDB1 protein expression was significantly associated with poor survival and was related to TNM stage. (PMID:28913972)
• Smad3-mediated recruitment of SETDB1 controls Snail1 expression and epithelial-mesenchymal transition in ductal breast carcinoma. (PMID:29233829)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	setdb1b	ENSDARG00000099021
mus_musculus	Setdb1	ENSMUSG00000015697
rattus_norvegicus	Setdb1	ENSRNOG00000021143
drosophila_melanogaster	ash1	FBGN0005386
drosophila_melanogaster	trr	FBGN0023518
drosophila_melanogaster	Set2	FBGN0030486
drosophila_melanogaster	CG4565	FBGN0037841
drosophila_melanogaster	G9a	FBGN0040372
drosophila_melanogaster	egg	FBGN0086908
caenorhabditis_elegans	set-32	WBGENE00008062
caenorhabditis_elegans		WBGENE00008206
caenorhabditis_elegans		WBGENE00008527
caenorhabditis_elegans		WBGENE00011729
caenorhabditis_elegans	met-1	WBGENE00016603
caenorhabditis_elegans		WBGENE00018023
caenorhabditis_elegans		WBGENE00019584
caenorhabditis_elegans		WBGENE00019690
caenorhabditis_elegans		WBGENE00019883
caenorhabditis_elegans		WBGENE00020006
caenorhabditis_elegans		WBGENE00020919
caenorhabditis_elegans		WBGENE00021282

Paralogs (19): KMT2C (ENSG00000055609), SETD1A (ENSG00000099381), SUV39H1 (ENSG00000101945), EZH2 (ENSG00000106462), EZH1 (ENSG00000108799), NSD2 (ENSG00000109685), ASH1L (ENSG00000116539), KMT2A (ENSG00000118058), SETDB2 (ENSG00000136169), SETD1B (ENSG00000139718), NSD3 (ENSG00000147548), SETBP1 (ENSG00000152217), SUV39H2 (ENSG00000152455), NSD1 (ENSG00000165671), KMT2D (ENSG00000167548), EHMT1 (ENSG00000181090), SETD2 (ENSG00000181555), EHMT2 (ENSG00000204371), KMT2B (ENSG00000272333)

Protein

Protein identifiers

Histone-lysine N-methyltransferase SETDB1 — Q15047 (reviewed: Q15047)

Alternative names: ERG-associated protein with SET domain, Histone H3-K9 methyltransferase 4, Lysine N-methyltransferase 1E, SET domain bifurcated 1

All UniProt accessions (9): Q15047, A0A8I5KT93, B0QZE6, E9PAP1, E9PQM8, E9PRF4, E9PS59, X6R732, X6RHV1

UniProt curated annotations — full annotation on UniProt →

Function. Histone methyltransferase that specifically trimethylates ‘Lys-9’ of histone H3 (H3K9me3). H3 ‘Lys-9’ trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. H3 ‘Lys-9’ trimethylation is coordinated with DNA methylation. Forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone ‘Lys-9’ trimethylation. Its activity is dependent on MBD1 and is heritably maintained through DNA replication by being recruited by CAF-1. SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by KRAB zinc-finger proteins. Required for HUSH-mediated heterochromatin formation and gene silencing. Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells. Required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs). In ESCs, in collaboration with TRIM28, is also required for H3K9me3 and silencing of endogenous and introduced retroviruses in a DNA-methylation independent-pathway. Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing. The SETDB1-TRIM28-ZNF274 complex may play a role in recruiting ATRX to the 3’-exons of zinc-finger coding genes with atypical chromatin signatures to establish or maintain/protect H3K9me3 at these transcriptionally active regions. Also catalyzes mono- and dimethylation of ‘Lys-9’ of free histone H3 (H3K9me1 and H3K9me2) during translation in the cytoplasm, which is then transported to the nucleus and incorporated into nucleosomes. Lacks all domains required for histone methyltransferase activity.

Subunit / interactions. Part of a complex containing at least CDYL, REST, WIZ, SETDB1, EHMT1 and EHMT2. Forms a complex with ATRX, TRIM28 and ZNF274. Probably part of a corepressor complex containing ZNF304, TRIM28, SETDB1 and DNMT1. Interacts with TRIM28/TIF1B. Interacts with ATF7IP and ATF7IP2; the interaction with ATF7IP protects SETDB1 from proteasomal degradation and is required to stimulate histone methyltransferase activity and facilitate the conversion of dimethylated to trimethylated H3 ‘Lys-9’. Interacts with CBX1 and CBX5. Interacts with DNMT3A and DNMT3B. Interacts with SUMO2. Interacts with MPHOSPH8. Interacts with ERG. Interacts with HDAC1, HDAC2, SIN3A and SIN3B. Interacts with ATRX. Interacts with RESF1. Interacts with ZNF638. Interacts with TASOR. Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression. Interacts with PHF13; the interaction probably enhances SETDB1 chromatin-associated levels and activity. Interacts with VRK1.

Subcellular location. Nucleus. Cytoplasm. Chromosome.

Tissue specificity. Widely expressed. High expression in testis.

Post-translational modifications. Degraded by the proteasome, shielded by interaction with ATF7IP. Monoubiquitinated at Lys-867 by E2 enzymes of the UBE2E family. The conjugated-Ub is protected from deubiquitination by the SET domain. Monoubiquitination at Lys-867 is required for catalytic activity, H3K9 methylation and endogenous retrovirus silencing.

Domain organisation. The Tudor domains recognize and bind histone H3 methylated at ‘Lys-9’ and acetylated at ‘Lys-14’ (H3K9me and H3K19ac, respectively). The Tudor domain 3 specifically recognizes H3K9me1 or H3K9me2, while the Tudor domain 2 specifically recognizes H3K9me3. H3K14ac is recognized by residues from Tudor domains 2 and 3, and the linker between them. The Tudor domain 1 contains an incomplete aromatic cage and is inactive. The pre-SET, SET and post-SET domains are all required for methyltransferase activity. The 347-amino-acid insertion in the SET domain has no effect on the catalytic activity. In the pre-SET domain, Cys residues bind 3 zinc ions that are arranged in a triangular cluster; some of these Cys residues contribute to the binding of two zinc ions within the cluster.

Miscellaneous. Highly up-regulated in Huntington disease patients, suggesting that participates in the altered chromatin modulation and transcription dysfunction observed in Huntington disease. Its down-regulation has salubrious effects on patients, suggesting that it may be a promising treatment in Huntington disease patients.

Similarity. Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. Suvar3-9 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q15047-1	1	yes
Q15047-2	2
Q15047-3	3

RefSeq proteins (14): NP_001138887, NP_001230420, NP_001353346, NP_001353347, NP_001380887, NP_001380888, NP_001380889, NP_001380890, NP_001380893, NP_001380894, NP_001380895, NP_001380896, NP_001380897, NP_036564 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001214	SET_dom	Domain
IPR001739	Methyl_CpG_DNA-bd	Domain
IPR002999	Tudor	Domain
IPR003616	Post-SET_dom	Domain
IPR007728	Pre-SET_dom	Domain
IPR016177	DNA-bd_dom_sf	Homologous_superfamily
IPR025796	Hist-Lys_N-MeTrfase_SETDB1	Family
IPR040880	DUF5604	Domain
IPR041291	TUDOR_5	Domain
IPR041292	Tudor_4	Domain
IPR046341	SET_dom_sf	Homologous_superfamily
IPR047232	SETDB1/2-like_MBD	Domain
IPR051516	SETDB_methyltransferase	Family

Pfam: PF00856, PF01429, PF05033, PF18300, PF18358, PF18359

Enzyme classification (BRENDA):

• EC 2.1.1.355 — [histone H3]-lysine9 N-trimethyltransferase (BRENDA: 12 organisms, 83 substrates, 52 inhibitors, 11 Km, 11 kcat entries)
• EC 2.1.1.366 — [histone H3]-N6,N6-dimethyl-lysine9 N-methyltransferase (BRENDA: 3 organisms, 7 substrates, 18 inhibitors, 4 Km, 4 kcat entries)
• EC 2.1.1.368 — [histone H3]-lysine9 N-dimethyltransferase (BRENDA: 6 organisms, 10 substrates, 20 inhibitors, 8 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
S-ADENOSYL-L-METHIONINE	0.53–0.68	4
HISTONE H3	0.0003–0.0009	2
S-ADENOSYL-L-METHIONINE	0.52–0.66	2
[HISTONE H3 PEPTIDE 1-15]-N6,N6-DIMETHYL-L-LYSIN	0.39–0.43	2
[HISTONE H3 PEPTIDE 1-15]-L-LYSINE9	0.28–0.41	2
[HISTONE H3 PEPTIDE 1-15]-N6-METHYL-L-LYSINE9	0.41–0.59	2
BIOTINYL-MARTKQTARKSTGGKAPRKQ	0.0074	1
HISTONE H3 (1-13)	0.0011	1
HISTONE H3 (T11PHOS)	0.0006	1
HISTONE H3(K27A)	0.0002	1
HISTONE H3(K4A)	0.0002	1
HISTONE K4-ACETYLK9	0.0022	1
HISTONE K4-TRIMETHYLK9	0.0006	1
HISTONE K4AK9	0.0015	1
HISTONE H3 (S10PHOS)	—	0

Catalyzed reactions (Rhea), 3 shown:

• L-lysyl(9)-[histone H3] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60280)
• N(6),N(6)-dimethyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60288)
• L-lysyl(9)-[histone H3] + 2 S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl(9)-[histone H3] + 2 S-adenosyl-L-homocysteine + 2 H(+) (RHEA:64444)

UniProt features (101 total): binding site 17, strand 16, mutagenesis site 13, compositionally biased region 11, modified residue 9, cross-link 8, domain 7, helix 6, sequence variant 4, region of interest 3, splice variant 3, turn 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
6BHD	X-RAY DIFFRACTION	1.25
9CUX	X-RAY DIFFRACTION	1.27
6BHE	X-RAY DIFFRACTION	1.35
6BHI	X-RAY DIFFRACTION	1.4
6BHG	X-RAY DIFFRACTION	1.45
5KCO	X-RAY DIFFRACTION	1.47
9CUW	X-RAY DIFFRACTION	1.53
5KE2	X-RAY DIFFRACTION	1.56
5QT1	X-RAY DIFFRACTION	1.58
5QT2	X-RAY DIFFRACTION	1.59
4X3S	X-RAY DIFFRACTION	1.6
7CD9	X-RAY DIFFRACTION	1.6
6AU2	X-RAY DIFFRACTION	1.63
6BPI	X-RAY DIFFRACTION	1.64
5KCH	X-RAY DIFFRACTION	1.7
5KE3	X-RAY DIFFRACTION	1.7
3DLM	X-RAY DIFFRACTION	1.77
8UWP	X-RAY DIFFRACTION	1.77
6AU3	X-RAY DIFFRACTION	1.8
6BHH	X-RAY DIFFRACTION	1.85
8G5E	X-RAY DIFFRACTION	1.98
5KH6	X-RAY DIFFRACTION	2.05
7CAJ	X-RAY DIFFRACTION	2.2
8IYA	X-RAY DIFFRACTION	2.43
7C9N	X-RAY DIFFRACTION	2.47
7CJT	X-RAY DIFFRACTION	2.47

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15047-F1	66.45	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (17): 729; 729; 731; 735; 735; 741; 743; 781; 781; 785; 787; 792 …

Post-translational modifications (17): 112, 117, 120, 1025, 1066, 1170, 1170, 1178, 1178, 182, 182, 867, 1032, 1032, 1038, 1069, 1149

Mutagenesis-validated functional residues (13):

Position	Phenotype
268	decreased binding to h3k9me3 and h3k14ac without affecting binding to h3k9me1.
332	decreased binding to h3k9me2 and h3k14ac.
358	decreased binding to h3k9me2 and abolished binding to h3k9me1.
363	decreased binding to h3k9me2 and abolished binding to h3k9me1.
382	decreased binding to h3k9me1 without affecting binding to h3k9me2, h3k9me3 or h3k14ac.
388	abolished binding to h3k9me2 and h3k14ac.
729–731	abolishes methyltransferase activity.
866	no effect on k-867 ubiquitination.
867	not monoubiquitinated by ube2e. loss of methyltransferase activity.
868	no effect on k-867 ubiquitination.
1224	abolishes methyltransferase activity.
1226	abolishes methyltransferase activity.
1279	abolishes methyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-9843940	Regulation of endogenous retroelements by KRAB-ZFP proteins
R-HSA-9843970	Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization
R-HSA-74160	Gene expression (Transcription)
R-HSA-9842860	Regulation of endogenous retroelements

MSigDB gene sets: 173 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, MAZ_Q6, MODULE_503, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_DNA_METHYLATION_DEPENDENT_CONSTITUTIVE_HETEROCHROMATIN_FORMATION, ONKEN_UVEAL_MELANOMA_UP, BACOLOD_RESISTANCE_TO_ALKYLATING_AGENTS_DN, MODULE_195, KEGG_LYSINE_DEGRADATION, BOYAULT_LIVER_CANCER_SUBCLASS_G1_UP, SANSOM_APC_TARGETS_DN, MODULE_147, MODULE_98, KAMMINGA_EZH2_TARGETS, NOUZOVA_TRETINOIN_AND_H4_ACETYLATION

GO Biological Process (9): DNA methylation-dependent constitutive heterochromatin formation (GO:0006346), negative regulation of gene expression (GO:0010629), methylation (GO:0032259), heterochromatin organization (GO:0070828), transposable element silencing by heterochromatin formation (GO:0141005), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338), response to vitamin (GO:0033273), response to ethanol (GO:0045471)

GO Molecular Function (17): DNA binding (GO:0003677), chromatin binding (GO:0003682), zinc ion binding (GO:0008270), histone H3K9 methyltransferase activity (GO:0046974), histone H3K9me2/3 reader activity (GO:0062072), histone H3K14ac reader activity (GO:0140015), histone H3 methyltransferase activity (GO:0140938), histone H3K9 dimethyltransferase activity (GO:0140942), histone H3K9me2 methyltransferase activity (GO:0140947), histone H3K9 monomethyltransferase activity (GO:0140948), histone H3K9 trimethyltransferase activity (GO:0140949), promoter-specific chromatin binding (GO:1990841), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), histone methyltransferase activity (GO:0042054), metal ion binding (GO:0046872)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Regulation of endogenous retroelements	2
Chromatin modifying enzymes	1
Gene expression (Transcription)	1
Chromatin organization	1
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
histone H3K9 methyltransferase activity	4
cellular anatomical structure	3
constitutive heterochromatin formation	2
chromatin organization	2
binding	2
histone H3 reader activity	2
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
metabolic process	1
transposable element silencing	1
cellular component organization	1
response to nutrient	1
response to alcohol	1
nucleic acid binding	1
transition metal ion binding	1
protein-lysine N-methyltransferase activity	1
histone H3 methyltransferase activity	1
histone methyltransferase activity	1
chromatin binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
protein methyltransferase activity	1
histone modifying activity	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

4249 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SETDB1	TRIM28	Q13263	996
SETDB1	DNMT3A	Q9Y6K1	995
SETDB1	ATF7IP	Q6VMQ6	991
SETDB1	HDAC1	Q13547	981
SETDB1	DNMT3B	Q9UBC3	980
SETDB1	SUV39H1	O43463	975
SETDB1	CBX5	P45973	971
SETDB1	ZNF274	Q96GC6	970
SETDB1	DNMT1	P26358	959
SETDB1	EHMT2	Q96KQ7	949
SETDB1	ZKSCAN7	Q9P0L1	893
SETDB1	ATF7IP2	Q5U623	856
SETDB1	ATF7	P17544	819
SETDB1	KMT5B	Q4FZB7	812
SETDB1	KMT5C	Q86Y97	809

IntAct

229 interactions, top by confidence:

A	B	Type	Score
VHL	CUL2	psi-mi:“MI:0914”(association)	0.940
ODAD1	HGS	psi-mi:“MI:0914”(association)	0.850
CBX5	CHAF1A	psi-mi:“MI:0914”(association)	0.790
CHAF1A	CBX5	psi-mi:“MI:0914”(association)	0.790
BRK1	HSBP1	psi-mi:“MI:0914”(association)	0.740
VSX1	USP12	psi-mi:“MI:0914”(association)	0.730
SETDB1	AKT1	psi-mi:“MI:0915”(physical association)	0.720
AKT1	SETDB1	psi-mi:“MI:0403”(colocalization)	0.720
SETDB1	AKT1	psi-mi:“MI:2364”(proximity)	0.720
FAM9C	NDC80	psi-mi:“MI:0914”(association)	0.670
PHKG2	PRKAB2	psi-mi:“MI:0914”(association)	0.640
SETDB1	MBD1	psi-mi:“MI:0915”(physical association)	0.580
MBD1	SETDB1	psi-mi:“MI:0915”(physical association)	0.580
SETDB1	MPHOSPH8	psi-mi:“MI:0914”(association)	0.560
SETDB1	UBE2I	psi-mi:“MI:0915”(physical association)	0.550
SUMO2	SETDB1	psi-mi:“MI:0915”(physical association)	0.550
SETDB1	CDK4	psi-mi:“MI:0915”(physical association)	0.550
SETDB1	MRPL44	psi-mi:“MI:0915”(physical association)	0.550
SUV39H1	SETDB1	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	SEC16A	psi-mi:“MI:0914”(association)	0.530

BioGRID (318): SETDB1 (Affinity Capture-RNA), SETDB1 (Affinity Capture-RNA), SETDB1 (Two-hybrid), SETDB1 (Affinity Capture-Western), SETDB1 (Reconstituted Complex), SETDB1 (Affinity Capture-MS), ATP2A1 (Affinity Capture-MS), TTC1 (Affinity Capture-MS), EXOC4 (Affinity Capture-MS), ATF7IP (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), FAF2 (Affinity Capture-MS), CCDC85C (Affinity Capture-MS), EXOC5 (Affinity Capture-MS)

ESM2 similar proteins: A0FIN4, A2VD01, A9ZLX4, D2HNW6, D4A7U2, O88974, O94988, P10914, P14316, P15314, P16236, P17433, P17947, P23570, P23906, P49140, Q00IB7, Q13506, Q13905, Q15047, Q1LY51, Q3B7M3, Q3SZP0, Q3TTA7, Q3UWM4, Q4V7W5, Q5HYC2, Q5RJA1, Q5XJV7, Q61122, Q62722, Q6A098, Q6AI12, Q6BDS1, Q6DFR2, Q6GQL0, Q6PKU1, Q6ZMT4, Q6ZNC4, Q80TJ7

Diamond homologs: A0A1L7TZE5, A4IGY9, A7E2Z2, A8XI75, J9VWH9, O43463, O54864, O60016, O65312, O82175, O88491, O88974, O96028, P20659, P42124, P45975, P46995, P55200, P70351, P93831, Q03164, Q06ZW3, Q08BR4, Q08BS4, Q0VD24, Q15047, Q15910, Q24742, Q28CQ7, Q28D84, Q294B9, Q2NL30, Q32PH7, Q4PB36, Q4R381, Q4R3E0, Q4V863, Q53H47, Q5DW34, Q5F3W5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SETDB1	“form complex”	SETDB1/NLK/CHD7	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 200 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of transcription factors	5	21.8×	2e-03
SUMOylation of ubiquitinylation proteins	6	13.4×	2e-03
Dengue virus activates/modulates innate and adaptive immune responses	5	12.8×	4e-03
Regulation of TP53 Degradation	5	11.2×	7e-03
SUMOylation of transcription cofactors	6	11.1×	3e-03
Transcriptional regulation by RUNX2	5	9.7×	9e-03
SUMOylation of DNA damage response and repair proteins	7	7.8×	4e-03
TCF dependent signaling in response to WNT	7	6.3×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	5	13.6×	8e-03
protein import into nucleus	8	6.5×	8e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 8 cancer types — BRCA, CLLSLL, COAD, HCC, HNSC, PAAD, PLMESO, UCEC.

Clinical variants and AI predictions

ClinVar

107 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	17
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

3731 predictions. Top by Δscore:

Variant	Effect	Δscore
1:150926515:G:T	donor_gain	1.0000
1:150927692:T:A	acceptor_gain	1.0000
1:150927699:T:G	acceptor_gain	1.0000
1:150927699:TGCA:T	acceptor_loss	1.0000
1:150927699:TGCAG:T	acceptor_gain	1.0000
1:150927700:GCA:G	acceptor_loss	1.0000
1:150927701:CAG:C	acceptor_gain	1.0000
1:150927702:A:AG	acceptor_gain	1.0000
1:150927702:AGA:A	acceptor_gain	1.0000
1:150927702:AGAG:A	acceptor_gain	1.0000
1:150927703:G:GG	acceptor_gain	1.0000
1:150927703:G:T	acceptor_gain	1.0000
1:150927703:GA:G	acceptor_gain	1.0000
1:150927703:GAGG:G	acceptor_gain	1.0000
1:150927703:GAGGA:G	acceptor_gain	1.0000
1:150927971:CCAGG:C	donor_loss	1.0000
1:150927972:CAGGT:C	donor_loss	1.0000
1:150927973:AGGTG:A	donor_loss	1.0000
1:150927976:T:A	donor_loss	1.0000
1:150929962:ATTAG:A	acceptor_gain	1.0000
1:150930115:TCAG:T	donor_loss	1.0000
1:150930116:CAG:C	donor_loss	1.0000
1:150930117:AGG:A	donor_loss	1.0000
1:150930118:GG:G	donor_loss	1.0000
1:150930119:GTAA:G	donor_loss	1.0000
1:150930120:T:A	donor_loss	1.0000
1:150939973:AGGTA:A	donor_loss	1.0000
1:150939974:GGTA:G	donor_loss	1.0000
1:150939976:T:G	donor_loss	1.0000
1:150941314:T:G	acceptor_gain	1.0000

AlphaMissense

8510 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:150942629:T:C	L205P	1.000
1:150942631:G:C	G206R	1.000
1:150942632:G:A	G206D	1.000
1:150942634:A:G	K207E	1.000
1:150942636:G:C	K207N	1.000
1:150942636:G:T	K207N	1.000
1:150942637:A:G	K208E	1.000
1:150942639:G:C	K208N	1.000
1:150942639:G:T	K208N	1.000
1:150942641:G:C	R209T	1.000
1:150942642:A:C	R209S	1.000
1:150942642:A:T	R209S	1.000
1:150942652:T:A	W213R	1.000
1:150942652:T:C	W213R	1.000
1:150942653:G:C	W213S	1.000
1:150942654:G:C	W213C	1.000
1:150942654:G:T	W213C	1.000
1:150942661:G:C	G216R	1.000
1:150942662:G:A	G216D	1.000
1:150942668:T:A	L218H	1.000
1:150942668:T:C	L218P	1.000
1:150942673:G:C	A220P	1.000
1:150942873:T:A	V232E	1.000
1:150942878:T:C	F234L	1.000
1:150942879:T:C	F234S	1.000
1:150942879:T:G	F234C	1.000
1:150942880:T:A	F234L	1.000
1:150942880:T:G	F234L	1.000
1:150942903:T:C	L242P	1.000
1:150942915:A:C	H246P	1.000

dbSNP variants (sampled 300 via entrez): RS1000052516 (1:150948451 A>G,T), RS1000147782 (1:150955161 T>C), RS1000163232 (1:150937229 G>A), RS1000178568 (1:150954807 A>C,G,T), RS1000202141 (1:150941137 TG>T), RS1000300225 (1:150933761 C>T), RS1000362674 (1:150961400 C>T), RS1000387792 (1:150933980 T>C), RS1000579910 (1:150961423 C>T), RS1000610954 (1:150930302 C>T), RS1000622048 (1:150929912 T>C), RS1000650873 (1:150961754 T>C,G), RS1000690872 (1:150947752 G>A), RS1000742940 (1:150947458 G>A), RS1000771904 (1:150936896 G>A)

Disease associations

OMIM: gene MIM:604396 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000649_7	Chronic kidney disease	1.000000e-12
GCST001266_1	Melanoma	9.000000e-11
GCST005951_38	Body mass index	4.000000e-09
GCST007505_26	Nevus count or cutaneous melanoma	2.000000e-10
GCST008478_2	Neurological blood protein biomarker levels	3.000000e-12
GCST008526_76	Coffee consumption	9.000000e-06
GCST010148_2	Cutaneous squamous cell carcinoma	7.000000e-09
GCST011124_1	Caffeine consumption from tea	6.000000e-10
GCST011126_7	Caffeine consumption from coffee or tea	1.000000e-26
GCST90020028_623	Hip circumference adjusted for BMI	4.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004632	nevus count
EFO:0006781	coffee consumption measurement
EFO:1001927	cutaneous squamous cell carcinoma
EFO:0010091	tea consumption measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2321646 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 2.1.1.43 Histone methyltransferases (HMTs)

ChEMBL bioactivities

10 potent at pChembl≥5 of 24 total, top 10 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.10	Kd	80	nM	CHEMBL5569118
7.06	Kd	88	nM	CHEMBL5569118
6.68	Kd	210	nM	CHEMBL4449143
6.63	Kd	232	nM	CHEMBL5572139
5.80	Kd	1600	nM	CHEMBL4471748
5.66	IC50	2200	nM	S-ADENOSYLHOMOCYSTEINE
5.62	IC50	2400	nM	CHEMBL6151379
5.49	Kd	3260	nM	CHEMBL5564879
5.40	Kd	4000	nM	CHEMBL6163762
5.36	Kd	4400	nM	CHEMBL4471746

PubChem BioAssay actives

7 with measured affinity, of 110 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[[(3R,5R)-1-methyl-5-(4-phenylmethoxyphenyl)piperidin-3-yl]amino]-3-prop-2-enyl-5H-pyrrolo[3,2-d]pyrimidin-4-one	2094520: Binding affinity N-terminal his tagged wild type human SETDB1 (190 to 410 residues ) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by isothermal titration calorimetry	kd	0.0800	uM
3-methyl-2-[[(3R,5R)-1-methyl-5-(4-phenylmethoxyphenyl)piperidin-3-yl]amino]-5H-pyrrolo[3,2-d]pyrimidin-4-one	2094520: Binding affinity N-terminal his tagged wild type human SETDB1 (190 to 410 residues ) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by isothermal titration calorimetry	kd	0.2100	uM
N-[2-(diethylamino)ethyl]-2-[[5,7-dimethyl-6-[(2-methylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]sulfanyl]acetamide	2094518: Binding affinity to SETDB1 (unknown origin) assessed as dissociation constant by surface plasmon resonance analysis	kd	0.2320	uM
3-methyl-2-[[(3R,5R)-1-methyl-5-phenylpiperidin-3-yl]amino]-5H-pyrrolo[3,2-d]pyrimidin-4-one	2094520: Binding affinity N-terminal his tagged wild type human SETDB1 (190 to 410 residues ) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by isothermal titration calorimetry	kd	1.6000	uM
(2S)-2-amino-4-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]butanoic acid	1192332: Inhibition of SETDB1 (unknown origin) by HMT assay	ic50	2.2000	uM
7-chloro-2-[3-(dimethylamino)propyl]-1-(3-ethoxyphenyl)-1H-chromeno[2,3-c]pyrrole-3,9-dione	2094518: Binding affinity to SETDB1 (unknown origin) assessed as dissociation constant by surface plasmon resonance analysis	kd	3.2600	uM
3,5-dimethyl-2-[[(3R,5R)-1-methyl-5-phenylpiperidin-3-yl]amino]pyrrolo[3,2-d]pyrimidin-4-one	2094520: Binding affinity N-terminal his tagged wild type human SETDB1 (190 to 410 residues ) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by isothermal titration calorimetry	kd	4.4000	uM

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, affects cotreatment	6
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
sodium arsenite	decreases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	affects methylation	1
Vehicle Emissions	increases abundance, increases expression	1
Berberine	increases expression	1
Caffeine	decreases phosphorylation	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Gallic Acid	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cadmium Chloride	decreases expression	1
tert-Butylhydroperoxide	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

65 unique, capped per target: 64 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2330201	Binding	Inhibition of SETDB1 (unknown origin) using histone H3 (1 to 25) as substrate after 0.25 hrs by scintillation proximity assay in presence of [3H]-S-adenosylmethionine	Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors. — J Med Chem
CHEMBL4416353	ADMET	Inhibition of human SETDB1 expressed in sf9 insect cells assessed as reduction in methylated histone H3 full length level using histone H3 full length as substrate in presence of [3H] SAM incubated for 30 mins by scintillation counting	High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). — J Med Chem

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A6B8	SEES3-1V human SETDB1, clone1	Embryonic stem cell	Male
CVCL_A6B9	SEES3-1V human SETDB1, clone2	Embryonic stem cell	Male
CVCL_A6C0	SEES3-1V human SETDB1, clone3	Embryonic stem cell	Male
CVCL_D8A3	Ubigene A-549 SETDB1 KO	Cancer cell line	Male
CVCL_TK73	HAP1 SETDB1 (-) 1	Cancer cell line	Male
CVCL_TK74	HAP1 SETDB1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.