Sex Chromosomes, Epigenetics, and Neurobehavioral Disease

描述(由申请者提供)：项目摘要本研究计划的长期目标是确定神经行为疾病中涉及性别差异的表观遗传学机制。关于性别行为差异的基础研究揭示了两种机制。最有文献记载的是男性和女性胚胎和新生儿性腺激素循环水平的差异，这种差异塑造了神经细胞的迁移、连接和结构，并对许多成年人的行为负责。此外，性染色体基因本身与许多性二型性行为有关。后一种机制在人类中也有相似之处，其中X染色体基因与许多精神障碍有关。在这里，我们将询问内分泌干扰化合物双酚A(BPA)是否可以改变行为，如果是的话，它是否在候选X染色体基因上起到去甲基化的作用。在目标1中，我们将检验性染色体和性腺性别与双酚A一起对小鼠幼年社会行为的独立影响。在目标2中，我们将进行基因表达阵列来验证一组在神经发育过程中受到双酚A暴露影响的候选基因。在最终目的中，我们将询问候选基因启动子中的DNA甲基化状态是否受到BPA的影响，以及组蛋白甲基化是否也受到影响。我们将使用基因工程小鼠、分子、遗传和行为方法来揭示性染色体基因和双酚A之间的表观遗传相互作用。我们研究的目标是找到有助于诊断、治疗和预防精神疾病的基因和过程。了解神经行为疾病的表观遗传学和遗传学基础对于诊断、预防和治疗至关重要。在这里，我们关注的是环境因素双酚A，这是一种人造化学物质，能够通过几种机制影响基因转录，在发育过程中暴露在这种化学物质中可能会影响大脑组织。鉴于几种神经行为疾病的患病率存在很大的性别差异(例如，自闭症在男孩中的发生率是女孩的4倍)，我们专注于对行为性别差异背后的机制进行表观遗传修饰。

DESCRIPTION (provided by applicant): Project Summary The long term goal of this research program is to identify epigenetic mechanisms involved in sex differences in neurobehavioral diseases. Basic research on sex differences in behavior reveals two mechanisms. The best documented is differences in circulating levels of gonadal hormones in male versus female embryos and neonates which shape neuronal cell migration, connections and structures and are responsible for many adult behaviors. In addition, sex chromosome genes themselves are correlated with a number of sexually dimorphic behaviors. This latter mechanism has parallels in humans in which X-chromosome genes are linked to many mental disorders. Here we will ask whether the endocrine disrupting compound, bisphenol A (BPA), can modify behavior and if so whether it acts as a hypomethylator on candidate X-chromosome genes. In Aim 1 we will examine independent effects of sex chromosome and gonadal sex, in conjunction with BPA, on juvenile social behavior in mice. In Aim 2 we will conduct gene expression arrays to validate a set of candidate genes affected by BPA exposure during neural development. In the final aim we will ask if DNA methylation status in candidate gene promoters is affected by BPA and if histone methylation is likewise affected. We will use genetically engineered mice, molecular, genetic and behavioral methods to reveal epigenetic interactions between sex chromosome genes and BPA. The goal of our research is to find genes and processes that can help diagnose, treat and prevent mental illnesses. Understanding the epigenetic, as well as the genetic, bases for neurobehavioral diseases is essential for diagnosis, prevention and treatment. Here we focus on one environmental factor, bisphenol A, a man-made chemical that has the capacity to affect gene transcription through several mechanisms, and to which exposure during development may affect brain organization. Given the large sex differences in the prevalence of several neurobehavioral diseases (for example, autism is found 4 times more often in boys than in girls), we focus on epigenetic modification of mechanisms that underlie sex differences in behavior.