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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Brain / growth & development*
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Copulation / drug effects
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Copulation / physiology
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CpG Islands
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Cytidine / analogs & derivatives
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Cytidine / pharmacology
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DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
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DNA (Cytosine-5-)-Methyltransferases / deficiency
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / physiology*
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DNA Methylation*
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DNA Methyltransferase 3A
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DNA, Intergenic / genetics*
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Disorders of Sex Development / genetics*
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Disorders of Sex Development / physiopathology
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Estradiol / physiology
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Female
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Gene Expression Regulation, Developmental*
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Male
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Mice
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Microfilament Proteins / analysis
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Nerve Tissue Proteins / analysis
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / biosynthesis
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Phthalimides / pharmacology
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Preoptic Area / enzymology
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Preoptic Area / physiopathology*
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Protein Isoforms / biosynthesis
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Protein Isoforms / genetics
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Rats
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Rats, Sprague-Dawley
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Sex Characteristics*
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Sex Differentiation / physiology*
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Testosterone / pharmacology
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Testosterone / physiology
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Tryptophan / analogs & derivatives
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Tryptophan / pharmacology
Substances
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DNA, Intergenic
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Dnmt3a protein, mouse
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Microfilament Proteins
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Nerve Tissue Proteins
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Phthalimides
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Protein Isoforms
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RG108
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neurabin
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Testosterone
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Estradiol
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Cytidine
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pyrimidin-2-one beta-ribofuranoside
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Tryptophan
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DNA (Cytosine-5-)-Methyltransferases
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DNA Methyltransferase 3A
Associated data
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BioProject/275796
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GEO/GSE66203