Epigenetic status determines germ cell meiotic commitment in embryonic and postnatal mammalian gonads

Abstract

The meiotic cell cycle is required for production of fertilization-competent gametes. Germ cell meiotic commitment requires expression of Stimulated by retinoic acid gene 8 (Stra8), which is transcriptionally activated by retinoic acid (RA). Meiotic suppression in embryonic male germ cells is believed to result from sex-specific differences in CYP26B1-catalyzed RA metabolism in the developing gonads. Here we show in mice that RA-induced Stra8 transcription is epigenetically controlled and requires a co-activator that binds proximal to the RA response elements (RAREs) in the Stra8 promoter. Embryonic male germ cells exposed in utero to the class I/II histone deacetylase (HDAC) inhibitor, trichostatin-A (TSA), show premature Stra8 activation and meiotic entry without altered Cyp26bl expression. We also show that Stra8 expression is detectable and physiologically regulated in adult mouse ovaries. Further, oogenesis induction in adult females using TSA is associated with Stra8 activation, and these events are absent in mice deficient in the RA precursor vitamin A. Finally, all of the actions of TSA in premeiotic germ cells in vitro and in mouse ovaries in vivo can be reproduced with the small molecule HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA). Thus, the ability of RA to transcriptionally induce expression of the meiosis-commitment gene, Stra8, is epigenetically controlled and this process involves a novel co-activator that functions upstream of the RAREs. These events not only coordinate the sex-specific timing of meiotic entry during embryogenesis, but also contribute to the regulation of oogenesis in adult female mammals.

Retinoic acid induces Sertoli cell paracrine signals for spermatogonia differentiation but cell autonomously drives spermatocyte meiosis

“…We propose that RA-activated RAR/RXR heterodimers cell autonomously control STRA8 production in preleptotene spermatocytes, essentially through their binding to a DR2 located close to Stra8 gene TSS2, and thereby stably commit male GC to the meiotic cell cycle (33). Although our findings conclusively show that endogenous RA can be the long-searched meiosisinducing factor in postnatal male GC, it is possible that signals other than RA play this role in fetal female GC (36)(37)(38). In agreement with this proposal, both Stra8 expression and meiosis initiate normally in fetal ovaries devoid of RA (6).…”

Sex determination in mammalian germ cells: extrinsic versus intrinsic factors

“…This result would suggest that testicular somatic cells secrete a factor that at least helps germ cells avoid entry into meiosis. Another clue comes from very recent work showing that epigenetic modification, particularly histone deacetylation, may play some role in the avoidance of entry into meiosis (Wang & Tilly 2010).…”

“…Given this apparent correlation between 'open conformation' pluripotent cell types and the ability to respond to RA with the upregulation of Stra8, it is not surprising that treatment of gonads with the potent histone deactylase inhibitor, trichostatin A (TSA), leads to an increased propensity to express Stra8 (Wang & Tilly 2010). TSA alters the epigenetic status of a cell directly, increasing histone acetylation and thus making regulatory regions more 'open' or accessible to transcription factors (Toth et al 2004, Durcova-Hills et al 2008.…”

Epigenetic changes associated with oocyte aging

“…It has been well documented that these histone modifications play important roles in cell cycle progression, DNA replication and repair, transcriptional activity and chromosome stability [26][27][28]. Among all forms of histone modifications mentioned above, some of them such as acetylation, phosphorylation and methylation have been shown to be essential for mammalian oocyte development as they display a meiosis stage-dependent nature [29].…”