SET1COMPASS

SET1COMPASS (Complex of Proteins Associated with Set1) is a conserved multi-subunit histone methyltransferase complex that catalyzes methylation of lysine 4 on histone H3 (H3K4). It is best characterized as the enzymatic core responsible for depositing H3K4 methyl marks, which are associated with actively transcribed chromatin. In the budding yeast Saccharomyces cerevisiae, SET1COMPASS is recruited to promoters and gene bodies of active genes and interacts with the transcription machinery to couple histone modification to transcription. The complex exists in several conserved forms across eukaryotes; while the exact composition varies, it is generally composed of a catalytic Set1 subunit together with several regulatory/accessory proteins that stabilize the complex and influence substrate specificity and targeting.

In mammals, related complexes are built around a Set1-family methyltransferase (KMT2A-D/MLL1-4) and a shared regulatory module often referred to as the WRAD core (WDR5, RbBP5, ASH2L, DPY-30), along with lineage- and context-specific subunits. SET1COMPASS-like complexes establish and maintain H3K4 methylation states, with H3K4me3 predominantly occurring near transcription start sites of active genes, and H3K4me1/2 marking enhancers or broader transcriptional regions. The activity of SET1COMPASS is coordinated with RNA polymerase II elongation and the PAF1 complex, ensuring proper deposition of methyl marks during transcription.

The complex is essential for normal development and genome regulation in many organisms, and misregulation of H3K4 methylation by SET1COMPASS can disrupt gene expression programs and contribute to disease states. It remains an active area of research to delineate subunit-specific roles and regulatory mechanisms across species.