title: Histone deacetylation during brain development is essential for permanent masculinization of sexual behavior.
abstract: Epigenetic histone modifications are emerging as important mechanisms for conveyance of and maintenance of effects of the hormonal milieu to the developing brain. We hypothesized that alteration of histone acetylation status early in development by sex steroid hormones is important for sexual differentiation of the brain. It was found that during the critical period for sexual differentiation, histones associated with promoters of essential genes in masculinization of the brain (estrogen receptor α and aromatase) in the medial preoptic area, an area necessary for male sexual behavior, were differentially acetylated between the sexes. Consistent with these findings, binding of histone deacetylase (HDAC) 2 and 4 to the promoters was higher in males than in females. To examine the involvement of histone deacetylation on masculinization of the brain at the behavioral level, we inhibited HDAC in vivo by intracerebroventricular infusion of the HDAC inhibitor trichostatin A or antisense oligodeoxynucleotide directed against the mRNA for HDAC2 and -4 in newborn male rats. Aspects of male sexual behavior in adulthood were significantly reduced by administration of either trichostatin A or antisense oligodeoxynucleotide. These results demonstrate that HDAC activity during the early postnatal period plays a crucial role in the masculinization of the brain via modifications of histone acetylation status.
authors.affiliation: Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan. matsuken@koto.kpu-m.ac.jp
authors.forename: Ken Ichi
authors.initials: KI
authors.lastname: Matsuda
authors.forename: Hiroko
authors.initials: H
authors.lastname: Mori
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Nugent
authors.forename: Donald W
authors.initials: DW
authors.lastname: Pfaff
authors.forename: Margaret M
authors.initials: MM
authors.lastname: McCarthy
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kawata
mesh_terms: D000107:Acetylation; D000818:Animals; D000831:Animals, Newborn; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D057967:Infusions, Intraventricular; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology; D011301:Preoptic Area / Q000254:growth & development / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D012733:Sex Differentiation; D012726:Sexual Behavior, Animal / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D020319:Oligodeoxyribonucleotides, Antisense; D001141:Aromatase; C559944:HDAC4 protein, rat; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases