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然未知。虽然环境因素可能影响其发病，但家族性研究表明，精神分裂症、自闭症、抑郁症、双相情感障碍和其他疾病都有可变但很强的遗传成分。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一小部分临床病例。这表明疾病的重要决定因素在其他地方。在这里，我们提出3型脱碘酶基因（Dio3）的表观遗传改变，无论是由当前环境因素引起的还是遗传自前代的，都可能导致与神经系统疾病相关的脑表型。由于Dio3严格控制甲状腺激素在发育和成人大脑中的可用性，其表达水平对于确保甲状腺激素的不同，适当的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

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.