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

描述(由申请人提供)：许多神经发育障碍的病因在很大程度上仍不清楚。尽管环境因素可能会影响它们的发病，但家族性研究表明，精神分裂症、自闭症、抑郁症、躁郁症和其他疾病，都有可变但强烈的遗传成分。然而，通过遗传连锁分析和转基因动物模型确定的这些疾病的候选基因只能解释很低比例的临床病例。这表明，疾病的重要决定因素存在于其他地方。在这里，我们认为，3型脱碘酶基因(Dio3)的表观遗传改变，无论是由当前的环境因素引起的，还是从前几代遗传来的，都可能导致与神经疾病相关的脑表型。由于Dio3严格控制着发育中和成人大脑中甲状腺激素的供应，其表达水平对于确保不同的、适当的甲状腺激素活动水平和正常的基因表达模式至关重要。Dio3在中枢神经系统中高度表达，其在该组织中的作用是 很可能在临床环境中被忽视了。甲状腺激素异常的临床诊断是基于血清参数。然而，Dio3表达的变化可以显著改变大脑中甲状腺激素的作用，而不会明显改变这种激素的循环水平。在这个项目中，我们建议使用我们实验室创建或鉴定的几个小鼠模型，这些模型带有遗传和表观遗传学变化，影响Dio3的剂量和表达，从而影响甲状腺激素在大脑中的作用程度。在这些模型中，我们将确定几个对人类神经状况重要的参数，例如新生儿和成人大脑基因表达的模式、成人大脑形态和社会行为。此外，我们建议通过分析某些组织中由于发育过度暴露于甲状腺激素而产生的表观遗传标记来定义甲状腺激素的表观遗传足迹。我们期待着证明Dio3对大脑发育和功能具有重要作用，并且影响dio3剂量的表观遗传因素，从头开始或从前几代遗传，可以在遗传完整的个体中产生显著的神经表型。这项工作可能会对我们理解神经疾病的易感性如何遗传产生重大影响，突出表观遗传信息在直接导致疾病或在遗传易感性个体中触发疾病方面的作用。最终，这项研究可能会导致新的基于表观遗传学的临床工具，用于风险评估，预防和应对某些神经疾病的治疗。

DESCRIPTION (provided by applicant): The etiology of many neurodevelopmental disorders remains largely unknown. Although environmental factors may influence their onset, familial studies have shown that schizophrenia, autism, depression, bipolar disorder, and others, all have a variable but strong genetic component. However, candidate genes for these conditions, as identified by genetic linkage analysis and transgenic animal models, can only explain a low percentage of clinical cases. This suggests that important determinants of disease lie elsewhere. Here we propose that epigenetic alterations in the type 3 deiodinase gene (Dio3), either caused by current environmental factors or inherited from previous generations, can lead to brain phenotypes of relevance to neurological disorders. As Dio3 tightly controls thyroid hormone availability across the developing and adult brain, its level of expression is critical to ensure distinct, appropriate levels of thyroid hormone action and normal patterns of gene expression. Dio3 is highly expressed in the central nervous system, and its role in this tissue is likely overlooked in the clinical setting. Clinical diagnosis of thyroid hormone abnormalities is based on serum parameters. However, alterations in Dio3 expression can markedly modify thyroid hormone action in the brain without noticeable changes in the circulating levels of the hormone. In this project, we propose to use several mouse models created or identified in our laboratory that carry genetic and epigenetic alterations affecting the dosage and expression of Dio3 and, thus, the degree of thyroid hormone action in the brain. In these models we will determine several parameters of importance to neurological conditions in humans, such as neonatal and adult patterns of brain gene expression, adult brain morphology and social behavior. In addition, we propose to define the epigenetic footprint of thyroid hormone by analyzing in certain tissues the epigenetic marks that result from developmental overexposure to thyroid hormone. We anticipate demonstrating that Dio3 has an important role for brain development and function and that epigenetic factors affecting Dio3 dosage, de novo or inherited from previous generations, can produce significant neurological phenotypes in genetically intact individuals. This work could have a major impact in our understanding of how susceptibility to neurological conditions can be inherited, highlighting the role of epigenetic information in directly causing disease or triggering it in genetically predisposed individuals. Ultimately, this research may lead to novel epigenetic-based clinical tools for risk assessment, prevention and response to treatment of certain neurological conditions.