MES-4: an autosome-associated histone methyltransferase that participates in silencing the X chromosomes in theC. elegansgerm line

Abstract

Germ cell development in C. elegans requires that the X chromosomes be globally silenced during mitosis and early meiosis. We previously found that the nuclear proteins MES-2, MES-3, MES-4 and MES-6 regulate the different chromatin states of autosomes versus X chromosomes and are required for germline viability. Strikingly, the SET-domain protein MES-4 is concentrated on autosomes and excluded from the X chromosomes. Here, we show that MES-4 has histone H3 methyltransferase (HMT) activity in vitro, and is required for histone H3K36 dimethylation in mitotic and early meiotic germline nuclei and early embryos. MES-4 appears unlinked to transcription elongation, thus distinguishing it from other known H3K36 HMTs. Based on microarray analysis, loss of MES-4 leads to derepression of X-linked genes in the germ line. We discuss how an autosomally associated HMT may participate in silencing genes on the X chromosome, in coordination with the direct silencing effects of the other MES proteins.

Trouble in transitioning: activation of zygotic transcription can lead to DNA breakage and genome instability

“…MES-4 is a histone methyltransferase that, among other functions, is required for X chromosome transcriptional silencing. 17,18 Previous work has shown that loss of MES-4 activates transcription on the X chromosomes, 17,18 and we were able to detect a clear H5 signal on the X chromosomes in Z2/Z3 after feeding in mes-4(RNAi) animals. 5 Importantly, mes-4 RNAi also caused a significant increase in RAD-51 foci formation on the X chromosome (2% in control samples, 29% in mes-4 (RNAi) samples).…”

Broad chromosomal domains of histone modification patterns in C. elegans

“…In-depth analysis in early embryos suggests instead that low H3K36me3 on X-linked genes reflects the distributions and activities of the two H3K36 histone methyltransferases, MES-4 and MET-1 ). MES-4, which can catalyze H3K36 methylation independently of RNA Pol II, associates preferentially with autosomal genes (Bender et al 2006;Rechtsteiner et al 2010). MET-1, which is presumed to depend on RNA Pol II like other H3K36 histone methyltransferases, can methylate genes on the X but is present at low levels in early embryos (Furuhashi et al 2010;Rechtsteiner et al 2010).…”

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.…”

“…The X chromosome is repressed by the activity of 2 classes of chromatin proteins: the Polycomb group (PcG) chromatin repressors E(Z) MES-2/MES-3 and MES-6 10 ; and the autosomeenriched proteins MES-4 and MRG-1. 11,34 The former impose H3K27 methylation on the X chromosome, leading to its silencing. The latter proteins methylate H3K36 on autosomes to prevent MES-2/3/6 binding.…”

“…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.…”