MCB Accepts, published online ahead of print on 27 April 2009

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Mol. Cell. Biol. doi:10.1128/MCB.00013-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Regulation of H3K4 trimethylation via Cps40 (Spp1) of COMPASS is monoubiquitination-independent: Implication for a Phe/Tyr switch by the catalytic domain of Set1

Yoh-Hei Takahashi, Jung Shin Lee, Selene K. Swanson, Anita Saraf, Laurence Florens, Michael P. Washburn, Raymond C. Trievel, and Ali Shilatifard^*

Stowers Institute for Medical Research, 1000 East 50^th Street, Kansas City, MO 64110; Department of Biological Chemistry, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0606, USA

^* To whom correspondence should be addressed. Email: ASH{at}Stowers.org.

The multi-protein complex, Set1/COMPASS, is the founding member of the histone H3 lysine 4 (H3K4) methyltransferases, whose human homologs include the MLL and hSet1 complexes. COMPASS can mono-, di-, and trimethylate H3K4, but transitioning to di- and trimethylation requires prior H2B monoubiquitination followed by recruitment of the Cps35 (Swd2) subunit of COMPASS. Another subunit, Cps40 (Spp1), directly interacts with Set1 and is only required for transitioning to trimethylation. To investigate how the Set1 and COMPASS subunits establish the methylation states of H3K4, we generated a homology model of the catalytic domain of yeast Set1 and identified several key residues within the Set1 catalytic pocket capable of regulating COMPASS's activity. We show that Tyr1052, a putative Phe/Tyr switch of Set1, plays an essential role in the regulation of H3K4 trimethylation by COMPASS and that the mutation to phenylalanine (Y1052F) suppresses the loss of Cps40 in H3K4 trimethylation levels, suggesting Tyr1052 functions together with Cps40. However, loss of H2B monoubiquitination is not suppressed by this mutation while Cps40 is stably assembled in COMPASS on chromatin, demonstrating that Tyr1052 and Cps40-mediated H3K4 trimethylation takes place following, and independently of, H2B monoubiquitination. Our studies provide a molecular basis for how H3K4 trimethylation is regulated by Tyr1052 and the Cps40 subunit of COMPASS.