title: Brain feminization requires active repression of masculinization via DNA methylation.
abstract: The developing mammalian brain is destined for a female phenotype unless exposed to gonadal hormones during a perinatal sensitive period. It has been assumed that the undifferentiated brain is masculinized by direct induction of transcription by ligand-activated nuclear steroid receptors. We found that a primary effect of gonadal steroids in the highly sexually dimorphic preoptic area (POA) is to reduce activity of DNA methyltransferase (Dnmt) enzymes, thereby decreasing DNA methylation and releasing masculinizing genes from epigenetic repression. Pharmacological inhibition of Dnmts mimicked gonadal steroids, resulting in masculinized neuronal markers and male sexual behavior in female rats. Conditional knockout of the de novo Dnmt isoform, Dnmt3a, also masculinized sexual behavior in female mice. RNA sequencing revealed gene and isoform variants modulated by methylation that may underlie the divergent reproductive behaviors of males versus females. Our data show that brain feminization is maintained by the active suppression of masculinization via DNA methylation.
authors.affiliation: 1] Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland, USA. [2] Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Nugent
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wright
authors.affiliation: Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Amol C
authors.initials: AC
authors.lastname: Shetty
authors.affiliation: Neuroscience Department, Mt. Sinai School of Medicine, New York, New York, USA.
authors.forename: Georgia E
authors.initials: GE
authors.lastname: Hodes
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Lenz
authors.affiliation: Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Anup
authors.initials: A
authors.lastname: Mahurkar
authors.affiliation: Neuroscience Department, Mt. Sinai School of Medicine, New York, New York, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.affiliation: Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Devine
authors.affiliation: 1] Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland, USA. [2] Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: McCarthy
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development*; D003307:Copulation / Q000187:drug effects / Q000502:physiology; D018899:CpG Islands; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D021901:DNA, Intergenic / Q000235:genetics*; D012734:Disorders of Sex Development / Q000235:genetics* / Q000503:physiopathology; D004958:Estradiol / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000032:analysis; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010797:Phthalimides / Q000494:pharmacology; D011301:Preoptic Area / Q000201:enzymology / Q000503:physiopathology*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D012733:Sex Differentiation / Q000502:physiology*; D013739:Testosterone / Q000494:pharmacology / Q000502:physiology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D000099273:Neurabins
chemical_list: D003562:Cytidine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D021901:DNA, Intergenic; D004958:Estradiol; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010797:Phthalimides; D020033:Protein Isoforms; D013739:Testosterone; D014364:Tryptophan; D000099273:Neurabins; C000715535:Dnmt3a protein, mouse; C503639:RG108; C009131:pyrimidin-2-one beta-ribofuranoside
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