Ovarian-Specific Transcription Networks Regulated by the TFIID Subunit TAF4b

Brown University, Providence RI

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Abstract

? DESCRIPTION (provided by applicant): Approximately 1% of the female population worldwide experiences primary ovarian insufficiency (POI) which results from a reduction of the ovarian follicle reserve that often leads to infertility. Although several genes have been found to be disrupted in women with POI, about 90% of the cases cannot be attributed to known genetic causes. By uncovering the cellular and molecular mechanisms underlying the development of the initial pool of primordial follicles and their maintenance in the adult ovary, we will be poise to better understand, diagnose and treat POI in the near future. We have discovered and characterized a protein called TAF4b that is essential for establishing and maintaining the ovarian follicle reserve in the mouse. TAF4b is a gonadal- enriched subunit of the general transcription factor TFIID, a large multiprotein complex composed of the TATA- box binding protein (TBP) and 14 TBP-associated factors (TAFs). Our approach to studying the regulation of ovarian follicle development by TAF4b has elucidated the ovarian functions of TAF4b in the context of a TAF4b-deficient mouse model. Collectively, these studies have revealed that TAF4b-deficient female mice suffer from hallmarks of POI including persistent estrous, elevated serum follicle stimulating hormone (FSH) and accelerated primordial follicle depletion. In addition to our own work, a number of additional studies have linked the potential function of TAF4b in the regulation of fertility in women. Together, these data implicate the potential deregulation of TAF4b-regulated processes in the context of human POI. Based on these complementary studies in humans and mice, we hypothesize that TAF4b-regulated transcriptional events in the mammalian oocyte and ovary serve to properly maintain normal ovarian aging and fertility. By uncovering the sub-ovarian functions and mechanisms of TAF4b in these studies, we aim to identify novel genes and expression mechanisms in place to ensure the successful production of high quality oocytes in women and perhaps one day better diagnose and/or manage patients with POI and other related deficits of ovarian health.