Histone Deacetylation during Brain Development Is Essential for Permanent Masculinization of Sexual Behavior
Histone Deacetylation during Brain Development Is Essential for Permanent Masculinization of Sexual Behavior
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DOI：
10.1210/en.2011-0193
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发表时间：
2011-07-01
期刊：
影响因子：
4.8
通讯作者：
Kawata, Mitsuhiro
中科院分区：
文献类型：
--
作者：
Matsuda, Ken Ichi;Mori, Hiroko;Kawata, Mitsuhiro
表观遗传组蛋白修饰正在成为将激素环境的作用传递和维持到发育中的大脑的重要机制。我们假设性类固醇激素在发育早期改变组蛋白乙酰化状态对大脑的性别分化很重要。结果发现，在性别分化的关键时期，组蛋白与必要基因的启动子在男性化的大脑（雌激素受体α和芳香化酶）在内侧视前区，男性性行为所必需的区域，差异乙酰化的性别之间。与这些发现相一致，组蛋白脱乙酰酶（HDAC）2和4的启动子的结合是男性高于女性。为了研究组蛋白去乙酰化在行为水平上对大脑男性化的参与，我们通过脑室内输注HDAC抑制剂阿司他丁A或针对新生雄性大鼠HDAC 2和-4 mRNA的反义寡核苷酸来抑制HDAC。成年期男性性行为的方面显着减少，无论是阿司他丁A或反义寡核苷酸的管理。这些结果表明，HDAC活性在出生后早期期间起着至关重要的作用，通过修改组蛋白乙酰化状态的大脑的雄性化。（内分泌学152：2760-2767，2011）
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 alpha 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. (Endocrinology 152: 2760-2767, 2011)