MCB Accepts, published online ahead of print on 24 August 2009

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Mol. Cell. Biol. doi:10.1128/MCB.00924-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II

Pengfei Wang, Chengqi Lin, Edwin R. Smith, Hong Guo, Brian W. Sanderson, Min Wu, Madelaine Gogol, Tara Alexander, Christopher Seidel, Leanne M. Wiedemann, Kai Ge, Robb Krumlauf, and Ali Shilatifard^*

Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA; Nuclear Receptor Biology Section, Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892; Department of Pathology & Laboratory Medicine, Kansas University Medical School, Kansas City, Kansas; Department of Anatomy & Cell Biology, Kansas University Medical School, Kansas City, Kansas

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

A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. The Set1/COMPASS was the founding member and the only H3K4 methylase in S. cerevisiae, however, in mammals at least six H3K4 methylases Set1A/B and MLL1-4 are found in COMPASS-like complexes capable of methylating H3K4. To gain further insight into the different roles and functional targets for the H3K4 methylases, we have undertaken a genome-wide analysis of H3K4 methylation patterns in wild-type Mll1^+/+ and Mll1^-/- mouse fibroblasts (MEFs). We found that Mll1 is required for the H3K4 trimethylation of less than 5% of promoters carrying this modification. Many of these genes, which include developmental regulators such as Hox genes, show decreased levels of RNA polymerase II recruitment and expression concomitant with the loss of H3K4 methylation. Although Mll1 is only required for the methylation of a subset of Hox genes, Menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/4 and/or the Set1 complexes have little to no effect on the Hox loci H3K4 methylation or expression levels in these MEFs. Together these data provide insight into redundancy and specialization of COMPASS-like complexes in mammals and provide evidence for a possible role for Mll1-mediated H3K4 methylation in the regulation of transcriptional initiation.