SETD1A
SET Domain Containing 1A, Histone Lysine Methyltransferase
Gene Information Card
| Symbol | SETD1A |
|---|---|
| Full Name | SET Domain Containing 1A |
| Gene Type | Protein coding |
| Chromosomal Location | 16p11.2 |
| NCBI Gene ID | 9739 ncbi.nlm.nih.gov/gene/9739 |
| Ensembl ID | ENSG00000099381 |
| UniProt ID | O15047 |
| OMIM ID | 611052 |
| HGNC ID | 29010 |
| Aliases | KMT2F, Set1, SET1, HsSet1, KIAA0339 |
Description
SETD1A is a catalytic subunit of the COMPASS-like complex that specifically methylates histone H3 at lysine 4 (H3K4), a mark associated with active transcription. It plays a critical role in embryonic development, cell cycle regulation, and DNA repair. Loss-of-function mutations are linked to neurodevelopmental disorders and various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Schizophrenia | Loss-of-function variants impair H3K4 methylation, disrupting neuronal gene expression | PMID: 25038753, ClinVar |
| Intellectual disability | De novo truncating mutations reduce COMPASS complex activity | PMID: 31006510, OMIM |
| Breast cancer | SETD1A overexpression promotes H3K4me3 at oncogene promoters | PMID: 28394336, COSMIC |
| Acute myeloid leukemia | SETD1A fusions (e.g., NUP98-SETD1A) drive leukemogenesis | PMID: 28115363, COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 15.2 | Medium |
| Brain | 10.8 | Medium |
| Bone marrow | 8.5 | Low |
| Liver | 6.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 12.1 | High expression |
| K562 | 9.4 | Moderate expression |
| MCF7 | 7.8 | Moderate expression |
| HepG2 | 5.2 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1685C>T (p.Pro562Leu) | Missense | <0.01% | Reduced catalytic activity; associated with schizophrenia |
| c.1234_1235del (p.Lys412Glufs*3) | Frameshift | Rare | Loss of function; intellectual disability |
| NUP98-SETD1A fusion | Chromosomal rearrangement | <0.1% | Oncogenic; acute myeloid leukemia |
Mutation functional classification
Loss of Function (LOF)
Truncating and missense mutations that reduce H3K4 methyltransferase activity are linked to neurodevelopmental disorders.
Gain of Function (GOF)
Overexpression or fusion proteins (e.g., NUP98-SETD1A) enhance H3K4me3 at target genes, promoting oncogenesis.
Dominant Negative (DN)
Not well characterized; some missense variants may interfere with COMPASS complex assembly.
View complete mutation data：
Gene Ontology (GO)
| • histone H3-K4 methyltransferase activity | • chromatin binding |
| • nucleus | • COMPASS complex |
| • regulation of transcription by RNA polymerase II |
Pathways
• H3K4 methylation
• COMPASS complex
• Transcriptional regulation by RUNX1
• Notch signaling
Protein Summary
SETD1A is a 1707-amino-acid protein containing an N-terminal RNA recognition motif, a central SET domain responsible for methyltransferase activity, and a C-terminal domain that mediates interaction with other COMPASS components. It is ubiquitously expressed and essential for maintaining active chromatin states at developmental genes.
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