| SET1A, also known as SETD1A or KMT2F, is a mammalian homolog of yeast Set1 and serves as the catalytic subunit of the SET1A/COMPASS histone H3 lysine 4 methyltransferase complex, which is essential for embryonic stem cell self-renewal, early development, and differentiation. SET1A has a conserved C-terminal SET domain that is crucial for its methyltransferase activity, primarily generating H3K4 di- and trimethylation, and is flanked by n-SET and post-SET domains, as well as regions that enable interactions with core subunits such as WDR5, RBBP5, ASH2L, and DPY30, collectively known as the WRAD complex, which greatly enhances its activity. It also partners with unique proteins like CFP1 for CpG island binding and WDR82 for linking to the RNA polymerase II C-terminal domain. SET1A’s main role is to deposit H3K4 trimethylation at promoters of active or poised genes, promoting an open chromatin state and transcriptional activation. Notably, while the SET domain is not required for embryonic stem cell proliferation or maintenance of pluripotency markers such as Nanog, Oct4, and Sox2 due to its non-catalytic scaffolding functions, it is indispensable for proper differentiation by driving H3K4 trimethylation at developmental genes including Bmp5, Epor, the HoxA gene cluster, and bivalent loci, supporting mesoderm specification, embryoid body formation, and preventing the abnormal persistence of pluripotency factors. During development, SET1A collaborates with MLL2 for stage-specific H3K4 trimethylation switching, with MLL2 acting in self-renewal and SET1A in differentiation, regulates Hox gene expression, and non-enzymatically supports mitotic fidelity and DNA repair. Mutations or loss of SET1A result in embryonic lethality at early stages, are linked to neurodevelopmental disorders such as autism and schizophrenia due to defects in H3K4 trimethylation, and its overexpression in cancers can enhance proliferation and invasion through pathways involving YAP, Wnt, and HIF1 alpha. |
