Caenorhabditis elegans chromatin-associated proteins SET-2 and ASH-2 are differentially required for histone H3 Lys 4 methylation in embryos and adult germ cells

Y. Xiao, C. Bedet, V.J. Robert, T. Simonet, S. Dunkelbarger, C. Rakotomalala, G. Soete, H.C. Korswagen, S. Strome, F. Palladino

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Abstract

Methylation of histone H3 lysine 4 (H3K4me), a mark associated with gene activation, is mediated by SET1 and the related mixed lineage leukemia (MLL) histone methyltransferases (HMTs) across species. Mammals contain seven H3K4 HMTs, Set1A, Set1B, and MLL1-MLL5. The activity of SET1 and MLL proteins relies on protein-protein interactions within large multisubunit complexes that include three core components: RbBP5, Ash2L, and WDR5. It remains unclear how the composition and specificity of these complexes varies between cell types and during development. Caenorhabditis elegans contains one SET1 protein, SET-2, one MLL-like protein, SET-16, and single homologs of RbBP5, Ash2L, and WDR5. Here we show that SET-2 is responsible for the majority of bulk H3K4 methylation at all developmental stages. However, SET-2 and absent, small, or homeotic discs 2 (ASH-2) are differentially required for tri- and dimethylation of H3K4 (H3K4me3 and -me2) in embryos and adult germ cells. In embryos, whereas efficient H3K4me3 requires both SET-2 and ASH-2, H3K4me2 relies mostly on ASH-2. In adult germ cells by contrast, SET-2 serves a major role whereas ASH-2 is dispensable for H3K4me3 and most H3K4me2. Loss of SET-2 results in progressive sterility over several generations, suggesting an important function in the maintenance of a functional germ line. This study demonstrates that individual subunits of SET1-related complexes can show tissue specificity and developmental regulation and establishes C. elegans as a model to study SET1-related complexes in a multicellular organism. [KEYWORDS: Animals, Caenorhabditis elegans/ physiology, Caenorhabditis elegans Proteins/ physiology, Embryo, Nonmammalian/ metabolism, Germ Cells/ metabolism, Histone-Lysine N-Methyltransferase/ physiology, Histones/ metabolism, Lysine/metabolism, Methylation, Nuclear Proteins/ physiology, Saccharomyces cerevisiae Proteins/physiology]
Original languageEnglish
Pages (from-to)8305-8310
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number20
DOIs
Publication statusPublished - 2011

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