Epigenetic Regulation of Premature Ovarian Senescence by TAF4b

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DESCRIPTION (provided by applicant): The condition of premature ovarian aging, or primary ovarian insufficiency, affects 1% of women under the age of 40, and can be induced by ovarian follicle disruption or depletion. General transcription factor TFIID-contained TBP-associated factor 4b (TAF4b) has recently been implicated in both humans and mice as critically important for fertility. TAF4b deficiency results in hallmarks of premature ovarian aging, including infertilty, poor oocyte quality, and dramatic gene expression changes. In addition, preliminary data shows an accelerated depletion of primordial follicles in neonatal TAF4b deficient ovaries, as well as epigenetic deregulation prior to depletion. At birth, TAF4b deficient ovaries appear to lose oocytes through caspase 3-dependent apoptosis, which likely leads to the ovarian senescence observed in reproductively mature mice. The aims of this proposal will explore in vivo and in vitro the ways in which TAF4b opposes ovarian senescence by transcriptionally regulating the oocyte epigenome. Aim 1 will test the oocyte autonomous role of TAF4b in preserving the primordial follicle pool. Aim 2 will explore the temporal role of TAF4b in regulation of the oocyte epigenome and transcriptional targets responsible for that regulation. This proposal will establish a unique mouse model as well as better elucidate molecular mechanisms underlying ovarian follicle maintenance and prevention of oocyte senescence and apoptosis.