Caenorhabditis elegans establishes germline versus soma by balancing inherited histone methylation

Abstract

Formation of a zygote is coupled with extensive epigenetic reprogramming to enable appropriate inheritance of histone methylation and prevent developmental delays. In C. elegans, this reprogramming is mediated by the H3K4me2 demethylase, SPR-5, and the H3K9 methyltransferase, MET-2. In contrast, the H3K36 methyltransferase, MES-4, maintains H3K36me2/3 at germline genes between generations to facilitate re-establishment of the germline. To determine whether the MES-4 germline inheritance pathway antagonizes spr-5; met-2 reprogramming, we examined the interaction between these two pathways. We find that the developmental delay of spr-5; met-2 mutant progeny is associated with ectopic H3K36me3 and the ectopic expression of MES-4 targeted germline genes in somatic tissues. Furthermore, the developmental delay is dependent upon MES-4 and the H3K4 methyltransferase, SET-2. We propose that MES-4 prevents critical germline genes from being repressed by antagonizing maternal spr-5; met-2 reprogramming. Thus, the balance of inherited histone modifications is necessary to distinguish germline versus soma and prevent developmental delay.

Maternal H3K36 and H3K27 HMTs protect germline immortality via regulation of the transcription factor LIN-15B

“…Furthermore, our genetic findings show that mes-4 mutants can develop a full-sized germline if they inherit X chromosomes that have a history of repression, demonstrating that MES-4 is not required for PGCs to launch a germline program. Interestingly, MES-4 is required for the mis-expression of germline genes in somatic tissues of several mutants, such as spr-5; met-2 , lin-15B , and mutants of DREAM complex components (Wang et al, 2005; Petrella et al, 2011; Carpenter et al, 2021). This suggests that maternal MES-4 has tissue-dependent roles in gene regulation.…”

“…mep-1, lin-15B, lin-35, and spr-5; met-2 mutants), and as a result, have developmental defects (Unhavaithaya et al, 2002; Wang et al, 2005; Cui et al, 2006; Petrella et al, 2011; Wu et al, 2012; Carpenter et al, 2021). Concomitant loss of MES-4 from these mutants prevents ectopic expression of germline genes and restores worm health (Wang et al, 2005; Cui et al, 2006; Petrella et al, 2011; Wu et al, 2012; Carpenter et al, 2021). In wild-type early embryos, MES-4 and methylated H3K36 associate with genes that were transcribed in the maternal germline, regardless of whether they are transcribed in embryos (Furuhashi et al, 2010; Rechtsteiner et al, 2010).…”

Gene bookmarking by the heat shock transcription factor programs the insulin-like signaling pathway

“…This question is underscored because, during normal development in all animals, chromatin modifications acquired during germline transcriptional activity are removed at fertilization to epigenetically reprogram the embryo (D'Urso and Brickner, 2017;Guo et al, 2017;Kaneshiro et al, 2019). These reprograming mechanisms remove marks of active gene expression that are added during normal germline transcription and, in some cases, also increase repressive marks at germline active genes to prevent their ectopic expression in subsequent generations (Andersen and Horvitz, 2007;Bessler et al, 2010;Carpenter et al, 2021;Rechtsteiner et al, 2019). Nevertheless, in many organisms, the memory of early-life stress exposure persists through meiosis and cycles of mitosis to alter later-life cellular programs through still poorly understood mechanisms (Brunet and Berger, 2014;D'Urso and Brickner, 2017;Leimar and McNamara, 2015;Sen et al, 2016).…”

“…As in many organisms, in the nematode Caenorhabditis elegans, environmental stressors that affect the parent also affect the unfertilized gametes. In C. elegans, epigenetic mechanisms that affect chromatin in one generation have been found to alter offspring lifespan and behavior in subsequent generations (Baugh and Day, 2020;Baugh and Hu, 2020;Camacho et al, 2018;Carpenter et al, 2021;Furuhashi et al, 2010;Greer et al, 2011Greer et al, , 2014Houri-Ze'evi et al, 2016;Jobson et al, 2015;Kaneshiro et al, 2019;Katz et al, 2009;Kerr et al, 2014;Kreher et al, 2018;Lev et al, 2017;Lim and Brunet, 2013;Minkina and Hunter, 2018;Moore et al, 2019;Posner et al, 2019;Rechavi et al, 2014;Tabuchi et al, 2018;Wan et al, 2021). In the parent, stress activates the heat shock transcription factor HSF1 (HSF-1 in C. elegans), which increases expression of protective heat-shock protein (hsp) genes to counteract stressinduced damage (Gomez-Pastor et al, 2018;Vihervaara et al, 2018).…”

“…HSF-1 recruits MET-2 to increase H3K9me2 levels at HSF-1 target genes in germ cells In C. elegans, epigenetic reprogramming of embryos occurs through the activities of the histone 3 lysine 4 (H3K4) demethylases SPR-5 and RBR-2, which remove H3K4me3 (H3K4 trimethyl) marks added at spermatogenesis genes during normal germline transcription (Carpenter et al, 2021;Christensen et al, 2007;Greer et al, 2014;Katz et al, 2009;Kerr et al, 2014;Nottke et al, 2011). These demethylases synergize with the putative methyltransferase MET-2, responsible for addition of repressive H3K9me1/2 (H3K9 mono-and di-methyl) modifications, and with other repressive methyltransferases together erase the memory of germline transcription to prevent ectopic gene expression in the next generation (Andersen and Horvitz, 2007;Bessler et al, 2010;Carpenter et al, 2021;Greer et al, 2014;Katz et al, 2009;Kerr et al, 2014;Rechtsteiner et al, 2019). Because adult offspring of stressed mothers were more stress resilient, we first considered the possibility that HSF-1-dependent transcription that occurred in heat-shocked mothers' germlines had somehow escaped germline reprogramming, allowing HSF-1 to preserve the memory of prior transcription and more readily increase expression of stress-protective hsp genes in the next generation.…”