The conserved RNA helicase YTHDC2 regulates the transition from proliferation to differentiation in the germline

Abstract

The switch from mitosis to meiosis is the key event marking onset of differentiation in the germline stem cell lineage. In Drosophila, the translational repressor Bgcn is required for spermatogonia to stop mitosis and transition to meiotic prophase and the spermatocyte state. Here we show that the mammalian Bgcn homolog YTHDC2 facilitates a clean switch from mitosis to meiosis in mouse germ cells, revealing a conserved role for YTHDC2 in this critical cell fate transition. YTHDC2-deficient male germ cells enter meiosis but have a mixed identity, maintaining expression of Cyclin A2 and failing to properly express many meiotic markers. Instead of continuing through meiotic prophase, the cells attempt an abnormal mitotic-like division and die. YTHDC2 binds multiple transcripts including Ccna2 and other mitotic transcripts, binds specific piRNA precursors, and interacts with RNA granule components, suggesting that proper progression of germ cells through meiosis is licensed by YTHDC2 through post-transcriptional regulation.

ketumutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2

“…Our findings agree well with recent independent studies of Ythdc2 function published while our manuscript was under review (Bailey et al, 2017;Hsu et al, 2017;Wojtas et al, 2017). In broad strokes, each study of Ythdc2 and of Meioc has led to the same general conclusion that the YTHDC2-MEIOC complex regulates the switch from mitotic divisions to meiosis (this work and Abby et al, 2016;Soh et al, 2017;Bailey et al, 2017;Hsu et al, 2017;Wojtas et al, 2017). STRA8 is a retinoic acid-induced factor that also regulates the mitosis to meiosis switch (Baltus et al, 2006;Anderson et al, 2008).…”

“…Moreover, the phenotypic outcomes in mutants differ, for example bam and bgcn mutant germ cells do not enter meiosis (McKearin and Spradling, 1990;Gonczy et al, 1997), whereas Meioc and Ythdc2 mutants do. Nonetheless, our findings and others' (Bailey et al, 2017;Hsu et al, 2017;Wojtas et al, 2017), along with the recent characterization of Meioc mutants (Abby et al, 2016;Soh et al, 2017), also establish intriguing parallels with bgcn and bam: in both mouse and fruit fly these genes play critical roles in the switch from mitotic cell cycles into meiosis, in both male and female germlines. On the basis of this similarity, and because members of both the YTHDC2/Bgcn and MEIOC/Bam families appear to be nearly ubiquitous in metazoans, we propose that the YTHDC2-MEIOC complex has an evolutionarily ancient and conserved function as a regulator of germ cell fate and differentiation.…”

“…The YTHDC2 domain architecture, with its RNA interaction modules and putative RNA helicase domains, as well as the cytoplasmic localization of the YTHDC2-MEIOC complex (this study and (Abby et al, 2016;Bailey et al, 2017;Soh et al, 2017)) leads to the obvious hypothesis that YTHDC2 regulates gene expression posttranscriptionally via direct interaction with specific RNA targets. Omega and the unrooted neighbor-joining trees were constructed from distances calculated using the scoredist function.…”

“…It has also been proposed that YTHDC2 promotes mRNA translation, based on effects of shRNA knockdown of YTHDC2 in human colon cancer cell lines (Tanabe et al, 2016), as well as measures of apparent translation efficiency of putative YTHDC2 targets in mouse testis and of artificial reporter constructs in HeLa cells (Hsu et al, 2017). An alternative possibility is that YTHDC2-MEIOC has translational suppressor activity based on analogy with Bgcn-Bam (Bailey et al, 2017), which has well documented translational inhibition functions in D. melanogaster germ cells (Li et al, 2009b;Shen et al, 2009;Kim et al, 2010;Insco et al, 2012;Li et al, 2013;Chen et al, 2014). Interestingly, MEIOC and/or YTHDC2 IP/MS experiments have also identified a number of proteins with roles in translation (Abby et al, 2016;Hsu et al, 2017;Wojtas et al, 2017).…”

Deciphering the ‘m6A code’ via quantitative profiling of m6A at single-nucleotide resolution

“…It is possible that the somewhat reduced proportion of the variability explained by our model in mESCs compared to yeast (35% vs. 50%) could be due to the fact that in yeast only a single YTH containing m6A reader is present (Schwartz et al, 2013) and no m6A demethylases have been documented to date. This contrasts with human, which express five different YTH containing readers (Bailey et al, 2017;Dominissini et al, 2012;Ivanova et al, 2017;Shi et al, 2017;Wang et al, 2014Wang et al, , 2015Zhu et al, 2014) , in addition to a growing number of proteins that have been implicated with an ability to read m6A (Edupuganti et al, 2017) , and two putative m6A demethylases (Jia et al, 2011;Mauer et al, 2016;Zheng et al, 2013) . MASTER-seq provides a fresh, quantitative lens for exploring the sources of variability in methylation levels within cells, and between conditions.…”