SETD2: SET Domain Containing 2, Histone Lysine Methyltransferase
A key epigenetic regulator in chromatin remodeling, tumor suppression, and renal cell carcinoma
Gene Information Card
| Symbol | SETD2 |
|---|---|
| Full Name | SET domain containing 2, histone lysine methyltransferase |
| Gene Type | Protein coding |
| Chromosomal Location | 3p21.31 |
| NCBI Gene ID | 29072 ncbi.nlm.nih.gov/gene/29072 |
| Ensembl ID | ENSG00000181555 |
| UniProt ID | Q9BYW2 |
| OMIM ID | 612778 |
| HGNC ID | 18420 |
| Aliases | HIF-1, HYPB, KMT3A, SET2, p231HBP |
Description
SETD2 encodes a histone methyltransferase that specifically trimethylates lysine 36 of histone H3 (H3K36me3), a mark associated with transcriptional elongation, DNA repair, and alternative splicing. It is the primary enzyme responsible for H3K36me3 in mammalian cells. Loss of SETD2 function is frequently observed in clear cell renal cell carcinoma and other cancers, contributing to genomic instability and altered gene expression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Clear cell renal cell carcinoma (ccRCC) | Inactivating mutations or loss of heterozygosity lead to loss of H3K36me3, promoting genomic instability and tumor progression. | PMID: 20601953, COSMIC |
| Lung adenocarcinoma | Somatic mutations and reduced expression correlate with poor prognosis. | PMID: 24755471 |
| Acute leukemia (AML) | Recurrent mutations in SETD2 contribute to leukemogenesis via defective DNA repair. | PMID: 24755471 |
| Luscan-Lumish syndrome | Germline heterozygous loss-of-function mutations cause overgrowth, intellectual disability, and autism. | OMIM #616831 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 28.5 | High |
| Kidney | 18.2 | Medium |
| Brain (cerebellum) | 15.1 | Medium |
| Heart | 12.3 | Medium |
| Liver | 8.7 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 (embryonic kidney) | 22.4 | High expression; commonly used for functional studies |
| A549 (lung carcinoma) | 14.6 | Moderate expression; mutations reported |
| 786-O (renal cell carcinoma) | 6.2 | Low expression; consistent with loss in ccRCC |
| K562 (leukemia) | 11.8 | Moderate expression; used in epigenetic studies |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.4886G>A (p.Arg1629Gln) | Missense | 1.2% in ccRCC (COSMIC) | Loss of methyltransferase activity |
| c.3667C>T (p.Arg1223*) | Nonsense | 0.8% in ccRCC | Truncation, loss of function |
| c.2071_2072insA (p.Thr691Asnfs*2) | Frameshift | 0.5% in ccRCC | Loss of function |
| c.1105G>T (p.Glu369*) | Nonsense | 0.3% in AML | Loss of function |
Mutation functional classification
Loss of Function (LOF)
Majority of SETD2 mutations in cancer are loss-of-function (nonsense, frameshift, splice-site, or missense in the SET domain), resulting in reduced or absent H3K36me3.
Gain of Function (GOF)
No well-characterized gain-of-function mutations reported in SETD2.
Dominant Negative (DN)
Rare; some missense mutations in the SET domain may exert dominant-negative effects by competing with wild-type protein, but evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • nucleus (GO:0005634) | • nucleoplasm (GO:0005654) |
| • zinc ion binding (GO:0008270) | • histone-lysine N-methyltransferase activity (GO:0018024) |
| • histone H3-K36 trimethylation (GO:0035098) | • positive regulation of transcription (GO:0045893) |
| • double-strand break repair (GO:0006302) | • mRNA processing (GO:0006397) |
Pathways
• Chromatin modifying enzymes (Reactome R-HSA-324485)
• Transcriptional regulation by small RNAs (Reactome R-HSA-5578749)
• H3K36me3-mediated DNA repair (PMID: 20601953)
Protein Summary
SETD2 is a 2564-amino-acid protein containing a catalytic SET domain, a post-SET domain, and multiple WW and coiled-coil domains. It catalyzes the trimethylation of histone H3 at lysine 36, a mark essential for transcriptional elongation, splicing regulation, and DNA damage response. The protein interacts with RNA polymerase II and is recruited to active transcription sites. Loss of SETD2 leads to global reduction of H3K36me3, increased genomic instability, and altered splicing patterns, contributing to oncogenesis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SETD2 Knockout HEK293 Cell Line | EDJ-KQ15234 | Human | 29072 | Details Get a Quote |
| SETD2 Knockout HCT 116 Cell Line | EDJ-KQ45902 | Human | 29072 | Details Get a Quote |
| SETD2 Knockout HeLa Cell Line | EDJ-KQ45903 | Human | 29072 | Details Get a Quote |
| SETD2 Knockout A-549 Cell Line | EDJ-KQ26274 | Human | 29072 | Details Get a Quote |
| SETD2 Knockout CNE-1 Cell Line | EDJ-KZ450 | Human | 29072 | Details Get a Quote |
