Histone-lysine N-methyltransferase SETD1A (SETD1A)

Histone-lysine N-methyltransferase SETD1A is a key catalytic component of the SET1/COMPASS-like complex, primarily responsible for the trimethylation of histone H3 at lysine 4 (H3K4me3), a chromatin mark associated with active gene transcription (UniProt P0C0S5). It plays a fundamental role in biological processes such as the G1/S cell cycle transition, DNA repair, and the maintenance of hematopoietic stem cells (PubMed: 28801120). In clinical contexts, SETD1A is a significant driver in various malignancies, including acute myeloid leukemia and breast cancer, where its overexpression promotes tumor cell proliferation (PubMed: 29335245). Furthermore, rare loss-of-function mutations in the SETD1A gene are strongly associated with neurodevelopmental disorders, particularly schizophrenia and intellectual disability (PubMed: 25363768). Although no specific SETD1A inhibitors are currently FDA-approved, it is an active area of drug discovery focusing on small-molecule inhibitors of its interaction with the scaffold protein WDR5 and the development of Proteolysis Targeting Chimeras (PROTACs) for targeted degradation (PubMed: 33619386).

Other names

SET domain containing 1ASET1AKMT2FLysine N-methyltransferase 2FSET1HSET1A

Disruption of the SET1/COMPASS complex by inhibiting the SETD1A-WDR5 interaction or targeted protein degradation via PROTACs to reduce H3K4me3 levels and suppress oncogenic gene expression.