SETDB2: A Histone Methyltransferase in Gene Silencing and Cancer
Comprehensive genomic and functional overview of SETDB2, a key regulator of chromatin and tumor suppression.
Gene Information Card
| Symbol | SETDB2 |
|---|---|
| Full Name | SET domain bifurcated histone lysine methyltransferase 2 |
| Gene Type | Protein coding |
| Chromosomal Location | 13q14.2 |
| NCBI Gene ID | 84652 ncbi.nlm.nih.gov/gene/84652 |
| Ensembl ID | ENSG00000139687 |
| UniProt ID | Q96T68 |
| OMIM ID | 607865 |
| HGNC ID | 25410 |
| Aliases | C13orf4, KMT1F, CLLD8 |
Description
SETDB2 is a histone methyltransferase that specifically catalyzes the trimethylation of histone H3 at lysine 9 (H3K9me3), a mark associated with transcriptional repression and heterochromatin formation. It plays critical roles in gene silencing, genomic stability, and development. Dysregulation of SETDB2 is implicated in various cancers and developmental disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Breast cancer | SETDB2 overexpression promotes H3K9me3-mediated silencing of tumor suppressor genes, enhancing proliferation and metastasis. | PMID: 25605248 |
| Colorectal cancer | Loss of SETDB2 leads to global hypomethylation and genomic instability, contributing to tumor progression. | PMID: 27323851 |
| Intellectual disability | De novo missense mutations in SETDB2 impair methyltransferase activity, disrupting neuronal gene regulation. | PMID: 31036916 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 15.2 | Medium |
| Brain | 8.7 | Low |
| Liver | 6.3 | Low |
| Breast | 4.1 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| MCF7 (breast cancer) | 12.5 | Overexpressed compared to normal |
| HEK293 (embryonic kidney) | 7.8 | Basal expression |
| HCT116 (colorectal cancer) | 5.2 | Reduced expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1234C>T (p.Arg412Trp) | Missense | <0.1% | Loss of methyltransferase activity |
| c.567_568del (p.Glu189fs) | Frameshift | <0.01% | Loss of function |
| c.2101G>A (p.Gly701Arg) | Missense | 0.05% | Gain of function (increased H3K9me3) |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations that truncate the SET domain abolish catalytic activity, leading to reduced H3K9me3 and derepression of target genes.
Gain of Function (GOF)
Missense mutations in the SET domain (e.g., p.Gly701Arg) enhance methyltransferase activity, increasing H3K9me3 and silencing tumor suppressors.
Dominant Negative (DN)
Not well characterized; some missense variants may interfere with wild-type SETDB2 dimerization, but evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • nucleus (GO:0005634) | • protein binding (GO:0005515) |
| • histone H3K9 methyltransferase activity (GO:0018024) | • chromatin organization (GO:0006325) |
| • negative regulation of transcription by RNA polymerase II (GO:0000122) | • histone methyltransferase complex (GO:0035097) |
Pathways
• hsa00310: Lysine degradation
• hsa05202: Transcriptional misregulation in cancer
• hsa05034: Alcoholism (histone modification)
Protein Summary
SETDB2 is a 778-amino acid protein containing a conserved SET domain responsible for its histone methyltransferase activity. It localizes to the nucleus and forms complexes with other chromatin modifiers to establish and maintain H3K9me3 marks. The protein is essential for silencing repetitive elements and regulating developmental genes. Structural studies reveal that the SET domain adopts a canonical fold, and mutations in this region disrupt substrate binding and catalysis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SETDB2 Knockout HEK293 Cell Line | EDJ-KQ9909 | Human | 83852 | Details Get a Quote |
| SETDB2 Knockout HeLa Cell Line | EDJ-KQ35599 | Human | 83852 | Details Get a Quote |
| SETDB2 Knockout A-549 Cell Line | EDJ-KQ36797 | Human | 83852 | Details Get a Quote |
| SETDB2 Knockout HCT 116 Cell Line | EDJ-KQ36798 | Human | 83852 | Details Get a Quote |
