Clustered PHD domains in KMT2/MLL proteins are attracted by H3K4me3 and H3 acetylation-rich active promoters and enhancers

Abstract

Histone lysine methyltransferase (KMT2) proteins form the core of COMPASS and COMPASS-like complexes that mediate transcriptional memory by methylating H3K4 at promoters and enhancers. KMT2A-D proteins, alternatively called mixed lineage leukaemia proteins (MLL1-4), contain highly conserved unique triplet and quartet of plant homeodomains (PHDs). Here, we show that clustered PHDs, expressed in isolation in HeLa cells, localize to well-defined loci of acetylation-rich active promoters and enhancers. Binding sites overlap with targets of full-length KMT2A (MLL1) and the COMPASS-like subunit WDR5, RbBP5 and with cell cycle and cancer-related genes. COSMIC data identify frequent variations in the PHDs of KMT2 proteins, particularly KMT2C, in a wide spectrum of malignancies. Changes are enriched at conserved positions within the PHDs, indicating that they cause loss-of-function mutations. Taken together, the biochemical and cancer data suggest that the PHDs contribute to KMT2A-D targeting to active promoters and enhancers.