In the November 19, 2012, online edition of the journal Genes & Development, researchers at the Stowers Institute for Medical Research report findings that may unveil the role of two human genes—MLL3 and MLL4—that are frequently mutated in certain cancers. In addition to its disease implications, the Stowers study exemplifies how the analysis of model organisms like yeast and fruit flies can illuminate human molecular biology. "We know that fundamental regulatory machineries are highly conserved from yeast to Drosophila to humans," says Stowers Investigator and the study's senior author, Ali Shilatifard, Ph.D., whose lab website describes projects in yeast, fruit flies, and mammalian species. "We use the awesome power of yeast and Drosophila genetics and biochemistry to define the molecular properties of these fundamentally important factors, and then test their function in human cells. In this study, these genes turned out to be frequently mutated in several different types of cancers." Over a decade ago, studies conducted by Shilatifard's laboratory identified an assembly of proteins known as Set1/COMPASS that biochemically modifies Histone 3 (H3) by planting methyl groups at a very precise location on the histone—namely lysine 4 (K4)—within chromosomes. H3K4 can be mono-, di-, or trimethylated by Set1/COMPASS. H3K4 trimethylation by Set1/COMPASS has now become the hallmark of actively transcribed genes from yeast to human. H3K4 can also be monomethylated, and this modification seems to be specific to enhancers, which are DNA elements that regulate gene expression in a tissue specific manner. "After we discovered yeast COMPASS, we found that human cells have the same machinery," says Shilatifard. "But rather than one COMPASS methylase, human cells bear six. The question became, why are there six COMPASS family members in human cells?" However, it has not been clear which COMPASS family member functions as monomethylase on enhancers.

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