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The Imitation Switch Protein SNF2L Regulates Steroidogenic Acute Regulatory Protein Expression during Terminal Differentiation of Ovarian Granulosa Cells

Molecular Medicine Program (M.A.L., D.J.P.) and Centre for Cancer Therapeutics (D.P., B.C.V.), Ottawa Health Research Institute, Ottawa, Ontario, Canada K1H 8L6; Facultad de Medicina Veterinaria y Zootecnia (N.P.), Universidad Autónoma del Estado de México, Toluca, México D.F., Mexico; Centre de Recherche en Reproduction Animale (B.D.M.), Faculté de Médecine Vétérinaire, Université de Montréal, St.-Hyacinthe, Quebec, Canada J2S 7C6; Departments of Cellular and Molecular Medicine, Obstetrics and Gynecology (D.P., B.C.V.), and Medicine, and Biochemistry, Microbiology, and Immunology (D.J.P.), University of Ottawa, Ontario, Canada K1H 8M5

Address all correspondence and requests for reprints to: Dr. David J. Picketts, Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. E-mail: dpicketts{at}ohri.ca.

Luteinization is a complex process, stimulated by gonadotropins, that promotes ovulation and development of the corpus luteum through terminal differentiation of granulosa cells. The pronounced expression of the mammalian imitation switch (ISWI) genes, SNF2H and SNF2L, in adult ovaries prompted us to investigate the role of these chromatin remodeling proteins during follicular development and luteinization. SNF2H expression is highest during growth of preovulatory follicles and becomes less prevalent during luteinization. In contrast, both SNF2L transcript and SNF2L protein levels are rapidly increased in granulosa cells of the mouse ovary 8 h after human chorionic gonadotropin treatment, and continue to be expressed 36 h later within the functional corpus luteum. We demonstrate a physical interaction between SNF2L and the progesterone receptor A isoform, which regulates progesterone receptor-responsive genes required for ovulation. Moreover, chromatin immunoprecipitation demonstrated that, after gonadotropin stimulation, SNF2L is associated with the proximal promoter of the steroidogenic acute regulatory protein (StAR) gene, a classic marker of luteinization in granulosa cells. Interaction of SNF2L with the StAR promoter is required for StAR expression, because small interfering RNA knockdown of SNF2L prevents the activation of the StAR gene. Our results provide the first indication that ISWI chromatin remodeling proteins are responsive to the LH surge and that this response is required for the activation of the StAR gene and the overall development of a functional luteal cell.

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