C. elegans is remarkable in that within the germ line of XX hermaphrodites, both X chromosomes are silent until the beginning of oogenesis. Methylation at specific lysine residues is one of several histone modifications that regulate chromatin access, to achieve either transcriptional activation or repression. The Maternal Effect Sterile proteins MES-2, MES-3, MES-4 and MES-6 are required for fertility. Recently we showed that MES-2, MES-3 and MES-6 function in a complex to methylate Lys27 of histone H3 in the germ line and in embryos (1). This repressive mark is concentrated on the Xs and is likely to help maintain them in a silent state. MES-4 also appears to regulate chromatin at the level of H3 tail methylation. Like MES-2 and other histone methyltransferases (HMTs), MES-4 has a SET domain. Staining with an antibody specific to H3 dimethylated at Lys36 showed this mark specifically decorates the autosomes, like MES-4 does (2). Significantly, in
mes-4 mutants, H3 dimeth-Lys36 is absent from the germ line and early embryos. We predict that H3 Lys36 methylation by MES-4 either directly promotes transcription of autosomal genes or protects the autosomes from MES-2/3/6-mediated repression, and thus helps focus repression on the Xs. Two findings favor the latter scenario. First, we tested whether MES-4, like the yeast H3 Lys36 HMT Set2p, participates in transcriptional elongation. MES-4-mediated methylation is independent of transcriptional elongation, and vice versa (see abstract by Suh & Strome). Second, we used microarray analysis to examine gene expression patterns in dissected
mes-4 germ lines. The predominant pattern is derepression of X-linked genes. Thus, silencing of the X chromosome in the germ line involves a complex interplay of histone modification activities. Little is known about the specific roles of mono-, di- and trimethylation of histones. Surprisingly,
mes-4 mutants appear normal for H3 trimeth-Lys36 although dimeth-Lys36 is undetectable. Thus, in the worm germ line, di- and trimethylation of H3 Lys36 appear to be catalyzed by different HMTs and to serve different functions. MES-4-mediated dimethylation of H3 Lys36 may protect nucleosomes from repressive methylations on nearby residues (e.g., Lys27). Our studies suggest that H3 trimeth-Lys36 mediated by another HMT is associated with transcriptional elongation (see abstract by Suh & Strome). 1 Bender et al., Current Biology 14:1639 (2004). 2 Fong et al., Science 296:2235 (2002).