Rosyln and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Prog Brain Res. 2010;186:77-95. doi: 10.1016/B978-0-444-53630-3.00006-3.
There are numerous examples of sex differences in brain and behavior and in susceptibility to a broad range of brain diseases. For example, gene expression is sexually dimorphic during brain development, adult life, and aging. These differences are orchestrated by the interplay between genetic, hormonal, and environmental influences. However, the molecular mechanisms that underpin these differences have not been fully elucidated. Because recent studies have highlighted the key roles played by epigenetic processes in regulating gene expression and mediating brain form and function, this chapter reviews emerging evidence that shows how epigenetic mechanisms including DNA methylation, histone modifications, and chromatin remodeling, and non-coding RNAs (ncRNAs) are responsible for promoting sexual dimorphism in the brain. Differential profiles of DNA methylation and histone modifications are found in dimorphic brain regions such as the hypothalamus as a result of sex hormone exposure during developmental critical periods. The elaboration of specific epigenetic marks is also linked with regulating sex hormone signaling pathways later in life. Furthermore, the expression and function of epigenetic factors such as the methyl-CpG-binding protein, MeCP2, and the histone-modifying enzymes, UTX and UTY, are sexually dimorphic in the brain. ncRNAs are also implicated in promoting sex differences. For example, X inactivation-specific transcript (XIST) is a long ncRNA that mediates X chromosome inactivation, a seminal developmental process that is particularly important in brain. These observations imply that understanding epigenetic mechanisms, which regulate dimorphic gene expression and function, is necessary for developing a more comprehensive view of sex differences in brain. These emerging findings also suggest that epigenetic mechanisms are, in part, responsible for the differential susceptibility between males and females that is characteristic of a spectrum of neurological and psychiatric disorders.
大脑和行为以及对广泛的大脑疾病的易感性存在许多性别差异的例子。例如，在大脑发育、成年期和衰老过程中，基因表达存在性别二态性。这些差异是由遗传、激素和环境影响的相互作用协调的。然而，支持这些差异的分子机制尚未完全阐明。由于最近的研究强调了表观遗传过程在调节基因表达和介导大脑形态和功能方面的关键作用，本章综述了新出现的证据，表明表观遗传机制如何包括 DNA 甲基化、组蛋白修饰和染色质重塑以及非编码 RNA(ncRNAs) 负责促进大脑中的性别二态性。在发育关键期暴露于性激素后，在性别二态性脑区如下丘脑发现 DNA 甲基化和组蛋白修饰的差异图谱。特定表观遗传标记的精细化也与调节生命后期的性激素信号通路有关。此外，甲基化-CpG 结合蛋白 MeCP2 和组蛋白修饰酶 UTX 和 UTY 等表观遗传因子的表达和功能在大脑中也存在性别二态性。ncRNAs 也参与促进性别差异。例如，X 失活特异性转录物（XIST）是一种长 ncRNA，可介导 X 染色体失活，这是一个重要的发育过程，在大脑中尤为重要。这些观察结果表明，了解调节性别二态性基因表达和功能的表观遗传机制对于全面了解大脑中的性别差异是必要的。这些新发现还表明，表观遗传机制部分负责神经和精神疾病谱中男性和女性之间差异易感性的特征。
