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Deoxyribonucleic Acid Methylation Controls Cell Type-Specific Expression of Steroidogenic Factor 1

Department of Biomedicine (E.A.H., L.A., R.A., H.L., A.E.L., M.B.), University of Bergen, 5009 Bergen, Norway; Stem Cells and Regeneration/Human Genetics Division (R.M.P.), Centre for Human Development, University of Southampton, Southampton SO16 6YD, United Kingdom; Endocrine Sciences Research Group (N.A.H.), University of Manchester & Manchester Biomedical Research Centre, Central Manchester & Manchester Children’s University Hospitals NHS Trust, Manchester M13 9PT, United Kingdom; and Departments of Internal Medicine and Pharmacology (N.R.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390

Address all correspondence and requests for reprints to: Marit Bakke, Department of Biomedicine, University of Bergen, Jonas Lies vei 9, 5009 Bergen, Norway. E-mail: marit.bakke{at}biomed.uib.no.

Steroidogenic factor 1 (SF1) is expressed in a time- and cell-specific manner in the endocrine system. In this study we present evidence to support that methylation of CpG sites located in the proximal promoter of the gene encoding SF1 contributes to the restricted expression pattern of this nuclear receptor. DNA methylation analyses revealed a nearly perfect correlation between the methylation status of the proximal promoter and protein expression, such that it was hypomethylated in cells that express SF1 but hypermethylated in nonexpressing cells. Moreover, in vitro methylation of this region completely repressed reporter gene activity in transfected steroidogenic cells. Bisulfite sequencing of DNA from embryonic tissue demonstrated that the proximal promoter was unmethylated in the developing testis and ovary, whereas it was hypermethylated in tissues that do not express SF1. Together these results indicate that the DNA methylation pattern is established early in the embryo and stably inherited thereafter throughout development to confine SF1 expression to the appropriate tissues. Chromatin immunoprecipitation analyses revealed that the transcriptional activator upstream stimulatory factor 2 and RNA polymerase II were specifically recruited to this DNA region in cells in which the proximal promoter is hypomethylated, providing functional support for the fact that lack of methylation corresponds to a transcriptionally active gene. In conclusion, we identified a region within the SF1/Sf1 gene that epigenetically directs cell-specific expression of SF1.

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