Journal
GENES & DEVELOPMENT
Volume 29, Issue 2, Pages 123-128Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.254870.114
Keywords
COMPASS; chromatin; epigenetics; histone H3 Lys4; methylation
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Funding
- Canadian Institutes of Health Research (CIHR) Banting and Best scholarship
- CIHR grant [MOP-136816]
- CIHR [MOP-89834]
- National Institutes of Health [R01GM069905]
- Pew Scholars Program in Biomedical Sciences
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The methyltransferase activity of the trithorax group (TrxG) protein MLL1 found within its COMPASS (complex associated with SET1)-like complex is allosterically regulated by a four-subunit complex composed of WDR5, RbBP5, Ash2L, and DPY30 (also referred to as WRAD). We report structural evidence showing that in WRAD, a concave surface of the Ash2L SPIa and ryanodine receptor (SPRY) domain binds to a cluster of acidic residues, referred to as the D/E box, in RbBP5. Mutational analysis shows that residues forming the Ash2L/RbBP5 interface are important for heterodimer formation, stimulation of MLL1 catalytic activity, and erythroid cell terminal differentiation. We also demonstrate that a phosphorylation switch on RbBP5 stimulates WRAD complex formation and significantly increases KMT2 (lysine [K] methyltransferase 2) enzyme methylation rates. Overall, our findings provide structural insights into the assembly of the WRAD complex and point to a novel regulatory mechanism controlling the activity of the KMT2/COMPASS family of lysine methyltransferases. Supplemental material is available for this article.
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