The MES-2/MES-3/MES-6 Complex and Regulation of Histone H3 Methylation in C. elegans

Abstract

The C. elegans proteins MES-2 and MES-6, orthologs of the Polycomb group (PcG) chromatin repressors E(Z) and ESC, exist in a complex with their novel partner MES-3. The MES system participates in silencing the X chromosomes in the hermaphrodite germline. Loss of maternal MES function leads to germline degeneration and sterility. We report here that the MES complex is responsible for di- and trimethylation of histone H3 Lys27 (H3-K27) in the adult germline and in early embryos and that MES-dependent H3-K27 marks are concentrated on the X's. Another H3-K27 HMT functions in adult somatic cells, oocytes, and the PGCs of embryos. In PGCs, the MES complex may specifically convert dimethyl to trimethyl H3-K27. The HMT activity of the MES complex appears to be dependent on the SET domain of MES-2. MES-2 thus joins its orthologs Drosophila E(Z) and human EZH2 among SET domain proteins known to function as HMTs (reviewed in ). Methylation of histones is important for long-term epigenetic regulation of chromatin and plays a key role in diverse processes such as X inactivation and oncogenesis. Our results contribute to understanding the composition and roles of E(Z)/MES-2 complexes across species.

A twist of fate: How a meiotic protein is providing new perspectives on germ cell development

“…Loss of either set of genes leads to transcription activation of X chromosome in the PGCs and eventual loss of germ cells in developing larvae. 10,11,34 In our analysis, we discovered that a significant fraction of xnd-1 embryos showed dramatic increase in the accumulation of H3K4me2 in the Z2/Z3. 15 The claim of increased accumulation of H3K4me2 in PGCs of xnd-1 mutant embryos is further strengthened by the misexpression of at least 2 neuronal markers in the germline of xnd-1 adults.…”

“…However, the X chromosome remains transcriptionally silenced in oocytes, a repression that is required for normal germ cell development. 10,11 XND-1 is among the earliest proteins to be expressed in the PGCs During early embryogenesis, germ cell determinants are segregated away from the somatic lineage. Both active localization to the P lineage and degradation in the somatic cells lead to PGC enrichment of key determinants including P-granules, NOS-2, and the transcriptional repressor PIE-1.…”

Genetics of germ cell development

“…Z2 and Z3 have lower levels of the activating histone modifications di-and tri-methyl lysine 4 on histone H3 (H3K4me2 and H3K4me3) and acetylated lysine 8 on histone H4 (H4K8ac), and slightly higher levels of the repressive modification trimethyl lysine 27 on histone H3 (H3K27me3). 45,46 A complex of maternaleffect proteins including the POLYCOMB group orthologs MES-2 and MES-6 is required for deposition of the repressive H3K27me3 mark in germ cells; individuals lacking any of these complex components have offspring that fail to develop a germline. [46][47][48] Likewise, loss of the LSD1 histone demethylase homolog spr-5 results in progressive failure to demethylate H3K4, impaired transcriptional repression, and cumulative sterility over multiple generations, while absence of the nanos homologs nos-1 and nos-2 causes premature reaccumulation of H3K4me2/3 in the embryonic germline and corresponding germline failure and sterility.…”

“…45,46 A complex of maternaleffect proteins including the POLYCOMB group orthologs MES-2 and MES-6 is required for deposition of the repressive H3K27me3 mark in germ cells; individuals lacking any of these complex components have offspring that fail to develop a germline. [46][47][48] Likewise, loss of the LSD1 histone demethylase homolog spr-5 results in progressive failure to demethylate H3K4, impaired transcriptional repression, and cumulative sterility over multiple generations, while absence of the nanos homologs nos-1 and nos-2 causes premature reaccumulation of H3K4me2/3 in the embryonic germline and corresponding germline failure and sterility. 45,49 In D. melanogaster, germ cell precursors lacking nanos or the spr-5/LSD1…”

gon-14 Functions With Class B and Class C Synthetic Multivulva Genes to Control Larval Growth in Caenorhabditis elegans

“…MES-2 and MES-6 associate with MES-3, a novel protein, to form the C. elegans analog of the Drosophila ESC-E(Z) and mammalian EED-EZH2 complexes (Paulsen et al 1995;Xu et al 2001;Cao and Zhang 2004). The MES-2,3,6/ESC-E(Z) complex has histone H3 Lysine27 (H3-K27) methyltransferase activity and represses transcription (Bender et al 2004b;Cao and Zhang 2004). In C. elegans, the complex maintains repressive di-and trimethyl H3-K27 marks on the X chromosome in the adult germline and in early embryos (Fong et al 2002;Bender et al 2004b) and spatially restricts expression of Hox genes in the soma (Ross and Zarkower 2003).…”