Epigenetic status determines germ cell meiotic commitment in embryonic and postnatal mammalian gonads.
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 Cyp26b1 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.
Wang
Ning
N
Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, and Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA.
Tilly
Jonathan L
JL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008540:Meiosis; D051379:Mice; D008810:Mice, Inbred C57BL; D009866:Oogenesis / Q000187:drug effects; D010053:Ovary / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D013737:Testis / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011506:Proteins; C102019:Stra8 protein, mouse; C012589:trichostatin A; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607081:Cyp26b1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase