Epigenetic Influence on Thyroid Hormone Action in the Brain and on Behavior

许多神经发育障碍的病因学，包括自闭症，精神分裂症和 注意力缺陷多动障碍仍然知之甚少。人们普遍认为，环境 可能涉及的因素，这些条件的遗传性相对较高。许多 在受影响人群中进行的流行病学和全基因组关联研究已经确定， 环境因素和候选基因增加了对这些条件的易感性。然而，在这方面， 这些遗传和环境因素只占临床病例的一小部分。 这表明，其他环境影响仍未确定，大多数 这些疾病的遗传成分是非遗传性的。 我们假设，大脑在发育过程中过度分泌甲状腺激素是一个重要的 因素有助于环境和非遗传遗传因素的病因学 神经发育障碍为了验证这一假设，我们将使用具有遗传和 DIO3的表观遗传缺陷，DIO3是控制甲状腺激素作用的主要大脑决定因素。在 具体目标#1，我们将确定Dio 3的等位基因特异性失活的后果是什么 在基因表达的大脑程序、成人大脑结构和 行为 在具体目标#2中，我们将描述胎儿和新生儿脑表达以及成人脑表达。 遗传上正常的小鼠后代的结构和行为， 在发育过程中甲状腺激素过量。我们将比较发展的结果， 大脑不同部位的基因表达与成年人的行为以及 暴露的祖先的表观基因组来定义哪些大脑发育程序，大脑区域，大脑 功能，以及受异常表观遗传影响的相关神经发育障碍 遗传起源于祖先对甲状腺激素过度分泌。 基于昼夜节律的异常调节， 神经发育障碍，也在缺乏Dio3基因的小鼠中观察到，我们将确定 甲状腺激素过多的分子和发育基础 导致生物钟编程异常（特定目标#3）。 我们期望我们的工作将大大推进我们对复杂性脑血管病的病因学的理解。 神经发育条件，并证明了突破性的概念，发展 甲状腺激素过多直接影响对这些疾病的易感性， 通过表观遗传机制间接遗传给后代。

The etiology of many neurodevelopmental disorders including autism, schizophrenia and attention-deficit hyperactive disorder remains poorly understood. It is accepted that environmental factors may be involved and that the heritability of those conditions is relatively high. Numerous epidemiological and genome-wide association studies in affected populations have identified environmental factors and candidate genes increasing the susceptibility to those conditions. However, those genetic and environmental factors can only account for a small percentage of the clinical cases. This suggests that additional environmental influences remain unidentified, and that the majority of the heritable component of those conditions is of non-genetic origin. We hypothesize that brain overexposure to thyroid hormone during development is an important factor contributing to both the environmental and non-genetic heritable components in the etiology of neurodevelopmental disorders. To test this hypothesis, we will use mouse models with genetic and epigenetic deficiency in DIO3, the main brain determinant controlling thyroid hormone action. In Specific Aim #1, we will determine what are the consequences of allele-specific inactivation of Dio3 globally or specifically in neurons for the brain programs of gene expression, adult brain structure and behavior. In Specific Aim #2, we will profile the fetal and neonatal brain expression and the adult brain structure and behavior of genetically normal mouse descendants of ancestral mice that were exposed to an excess of thyroid hormone during development. We will compare the results of developmental gene expression in different parts of the brain with their adult behavior and with the altered epigenome of exposed ancestors to define which brain developmental programs, brain regions, brain functions, and related neurodevelopmental disorders that are affected by abnormal epigenetic inheritance originated in ancestral overexposure to thyroid hormones. Based on the abnormal regulation of circadian rhythms that is typically associated with neurodevelopmental disorders and is also observed in mice lacking the Dio3 gene, we will identify the molecular and developmental basis by which developmental exposure to thyroid hormone excess leads to the abnormal programming of the circadian clock (Specific Aim #3). We anticipate that our work will greatly advance our understanding of the etiology of complex neurodevelopmental conditions and demonstrate the breakthrough concept that a developmental excess of thyroid hormone influences the susceptibility to those conditions directly in the present generation and indirectly in descendants via epigenetic mechanisms of inheritance.