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SETs in Epigenetics and Disease
SET-domain–containing proteins (SETs) are a family of enzymes that share a conserved SET domain, approximately 130 amino acids in length. This domain is characteristic of a large group of histone lysine methyltransferases (KMTs) and is named after the three Drosophila genes in which it was first identified: Su(var)3–9, Enhancer of zeste, and Trithorax. These enzymes regulate gene expression by methylating specific lysine residues on histone proteins, thereby modifying chromatin structure. As key epigenetic regulators, SET-domain proteins play essential roles in cell identity, developmental gene expression, DNA repair and replication, and are implicated in cancer and other diseases when mutated or dysregulated.
| Protein / Family | Epigenetic Function | Disease Association | Key Publications | Key Products |
|---|---|---|---|---|
| AKT | SETD7 methylation of AKT limits its nuclear translocation and signaling. Chromatin remodeling by SET proteins influences transcription of AKT pathway genes. | Cancer (breast, prostate, liver, lung, glioblastoma), Diabetes/metabolic disease and Cardiovascular disease. | Hayashi, et al., Breast Cancer Research. 2025 | |
| ASH2L | Non‑catalytic: helps scaffold H3K4 methyltransferase complexes, enabling methylation activity on H3K4 promoters. | Dysregulation of complex may contribute indirectly to cancers, developmental disorders. | Zhang et al. Circulation Research. 2025 | |
| KMT2A | KMT2A contains a SET domain at its C-terminus, which provides histone lysine methyltransferase activity. | Activates transcription of developmental genes, Supports stem cell identity, and Regulates HOX gene clusters. | Zehtabcheh et al., Biomark. Res. 2025 Wang et al., BMC Pediatr. 2025 |
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| p53 | Tumor suppressor protein and transcription factor. SET-domain lysine methyltransferases (KMTs) methylate p53 affecting its activity and stability. | Cancers(Leukemias, lymphomas, breast, colon, liver) and neurodegenerative disorders (altered SET activity can affect p53-linked apoptotic pathways). | Giaimo eta al., Cell. Mol. Life. Sci. 2024. | |
| PRC2 complex | Complex composed of Enhancer of zeste (E(z)) (represses genes during development), EZH2/EZH1 (Catalyzes H3K27me3 via its SET domain), EED (Binds H3K27me3 and helps stimulate EZH2 activity), SUZ12 (Essential for complex stability and activity). | Cancers (lymphomas, prostate, breast), Weaver syndrome, Myelodysplastic syndromes (epigenetic dysregulation via EZH2 loss-of-function) and Neurodevelopmental disorders. | Longhurst et al., eLife, 2025. | |
| SETD1A, SETDB1, SETD7, SETD2 | SETD1A - Adds methyl groups to histone H3 at lysine 4 (H3K4me1/2/3) associated with transcriptional activation and promoter competence. SETDB1 - Catalyzes H3K9me2/3, a repressive chromatin mark tied to gene silencing. SETD7 - Adds a methyl group (mono) to H3K4 and to other lysine residues on transcription factors. SETD2 - Catalyzes H3K36 trimethylation influencing gene bodies, transcription elongation, splicing and DNA repair. | Neurodevelopmental disorders (intellectual disability, developmental delay), neuropsychiatric (schizophrenia), Various cancers (glioma, melanoma, lung, breast, ovarian, prostate), and Cardiovascular diseases. | Zehtabcheh et al., Biomark. Res. 2025 | |
| SMYD3 | Methylates H3K4 (activating mark) and also some non‑histone proteins (AKT1 methylation) to modulate gene expression and signalling. | Colorectal cancer, hepatocellular carcinoma, oral squamous cell carcinoma and many other malignancies. BioMed Central+1 | Wang et sl., Proc. Natl. Acad. Sci. 2025 | |
| SUV39H1 | SUV39H1 contains a C-terminal SET domain responsible for its histone methyltransferase activity. | Establishes heterochromatin, Represses gene transcription by compacting chromatin and Maintains genomic stability and silences repeats. | Wang et al., PNAS. 2025 Kudithipudi et al., ACS Chem Biol. 2025 |
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| WDR5 | Acts as a “scaffolding”/reader protein that helps recruit methyltransferases to chromatin and stabilise the complex for H3K4 methylation. | Mutations or dysregulation of WDR5 impact epigenetic regulation; may be implicated in cancer. | Hoffmann et al., RSC Chemical Biology. 2025 |
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