Histone Methyltransferases MES-4 and MET-1 Promote Meiotic Checkpoint Activation in Caenorhabditis elegans

Abstract

Chromosomes that fail to synapse during meiosis become enriched for chromatin marks associated with heterochromatin assembly. This response, called meiotic silencing of unsynapsed or unpaired chromatin (MSUC), is conserved from fungi to mammals. In Caenorhabditis elegans, unsynapsed chromosomes also activate a meiotic checkpoint that monitors synapsis. The synapsis checkpoint signal is dependent on cis-acting loci called Pairing Centers (PCs). How PCs signal to activate the synapsis checkpoint is currently unknown. We show that a chromosomal duplication with PC activity is sufficient to activate the synapsis checkpoint and that it undergoes heterochromatin assembly less readily than a duplication of a non-PC region, suggesting that the chromatin state of these loci is important for checkpoint function. Consistent with this hypothesis, MES-4 and MET-1, chromatin-modifying enzymes associated with transcriptional activity, are required for the synapsis checkpoint. In addition, a duplication with PC activity undergoes heterochromatin assembly when mes-4 activity is reduced. MES-4 function is required specifically for the X chromosome, while MES-4 and MET-1 act redundantly to monitor autosomal synapsis. We propose that MES-4 and MET-1 antagonize heterochromatin assembly at PCs of unsynapsed chromosomes by promoting a transcriptionally permissive chromatin environment that is required for meiotic checkpoint function. Moreover, we suggest that different genetic requirements to monitor the behavior of sex chromosomes and autosomes allow for the lone unsynapsed X present in male germlines to be shielded from inappropriate checkpoint activation.

MBTD1 is associated with Pr-Set7 to stabilize H4K20me1 in mouse oocyte meiotic maturation

“…It accumulates on the methylated H4K20 dock at the DNA damage site and co-localizes with γH2AX to form the DNA repair complex. [27][28][29] However, in our study, when 53BP1 expression was decreased after MBTD1 or Pr-Set7 depletion, increased γH2AX foci were formed. We assumed that depletion of MBTD1 and Pr-Set7 would cause abrogation of H4K20me1, the substrate of H4K20me2 and H4K20me3 and binding sites of 53BP1, 30,31 thus resulting in decreased expression of 53BP1.…”

The Meiotic Checkpoint Network: Step-by-Step through Meiotic Prophase

“…Perhaps not surprisingly, MCN roles have also been reported for several histone methyltransferases (San-Segundo and Roeder 2000;Checchi and Engebrecht 2011;Lamelza and Bhalla 2012;Ontoso et al 2013a,b), which presumably promote chromosome axis assembly or contribute to the structural environment of MCN signaling. Further supporting an instructive role of the chromatin environment, differential chromatin marks on sex chromosomes and autosomes are associated with the differential response to asynapsis in C. elegans (Checchi and Engebrecht 2011;Lamelza and Bhalla 2012).…”

“…In many organisms, disruption of components of the meiotic chromosome axes, including SYCP3 and cohesins, leads to a defect in MCN signaling (Wang and Hoog 2006;Kouz-netsova et al 2009;Callender and Hollingsworth 2010;Lightfoot et al 2011), although in some cases the loss of signal has been attributed to reduced DSB formation (Callender and Hollingsworth 2010). Perhaps not surprisingly, MCN roles have also been reported for several histone methyltransferases (San-Segundo and Roeder 2000;Checchi and Engebrecht 2011;Lamelza and Bhalla 2012;Ontoso et al 2013a,b), which presumably promote chromosome axis assembly or contribute to the structural environment of MCN signaling. Further supporting an instructive role of the chromatin environment, differential chromatin marks on sex chromosomes and autosomes are associated with the differential response to asynapsis in C. elegans (Checchi and Engebrecht 2011;Lamelza and Bhalla 2012).…”

Meiosis

“…Induction of this apoptosis by unpaired PCs requires PCH-2 (Bhalla and Dernburg, 2005: PMID 16339446). Synapsis at PCs is monitored with the help of MES-4 and MET-1 (MES-4 alone for the X chromosome) (Lamelza and Bhalla, 2012: PMID 23166523).…”