A genome-wide approach to the epigenetics of stress and depression

描述（由申请人提供）：我们建议通过高度集中的方法，将尖端的表观基因组分析与基于压力的疾病小鼠模型相结合，确定表观遗传学对抑郁症（最常见的使人衰弱的精神疾病）的影响。众所周知，压力在引发重度抑郁症（MDD）方面发挥着重要作用，可能与遗传易感性因素相互作用。BDNF是一种在抑郁症和抗抑郁反应中起关键作用的基因，最近的研究表明应激介导的表观遗传控制为表观遗传机制可以介导这种相互作用提供了分子证据。约翰霍普金斯大学的一名共同研究者最近的研究表明，包括Bdnf在内的基因的DNA去甲基化在电惊厥刺激下的神经可塑性和神经发生中起作用。这些结果表明，对抑郁症的病因学和病理生理学以及治疗反应机制的新见解，可以从全基因组的表观遗传学方法中收集到研究应激诱导和药物逆转的啮齿动物大脑DNA变化的可能性。进行全基因组表观遗传学研究的工具才刚刚出现，我们在约翰霍普金斯大学的表观遗传学中心一直是开发此类工具的领导者，已经创建了用于全基因组DNA甲基化（DNAm）研究的相对甲基化综合杂交阵列（CHARM）方法。除了表观基因组学方面的专业知识外，我们的团队还在项目成功的其他方面拥有专业知识，包括啮齿动物压力模型、抑郁症遗传学和神经生物学。我们打算测试以下具体目标：1)通过抗抑郁药物治疗确定慢性社会压力的行为和内分泌结果及其持续性或可逆性；2)通过表观遗传修饰检验社会压力是否会导致抑郁样行为；3)通过研究基因表达、脑其他区域的DNAm、血液中的DNAm以及基因组蛋白修饰来验证和扩展顶级DNAm差异发现。

DESCRIPTION (provided by applicant): We propose to determine the epigenetic contribution to depression, the most common debilitating psychiatric disorder, through a highly focused approach that combines cutting-edge epigenomic analysis with a stress-based mouse model of the illness. Stress is known to play a major role in triggering major depressive disorder (MDD), likely through interaction with genetic vulnerability factors. Recent work showing stress-mediated epigenetic control of BDNF, a gene that plays a key role in depression and antidepressant response, provides molecular evidence that epigenetic mechanisms can mediate this interaction. Additional recent work from a Co- Investigator at Johns Hopkins shows that DNA demethylation of genes including Bdnf plays a role in neural plasticity and neurogenesis in response to electroconvulsive stimulation. These results suggest the possibility that new insights into the etiology and pathophysiology of depression, and into the mechanisms of treatment response, can be gleaned from a genome- wide epigenetic approach to the study of stress-induced, and medication reversed, changes in rodent brain DNA. The tools to perform genome-wide epigenetic studies have only just become available and our Epigenetics Center at Johns Hopkins has been a leader in the development of such tools, having created the Comprehensive Hybridization Arrays for Relative Methylation (CHARM) method for genome-wide DNA methylation (DNAm) studies. In addition to our epigenomics expertise, our team also has expertise in the other facets of this project that are crucial to its success, including rodent models of stress, the genetics of depression, and neurobiology. We intend to test the following specific aims: 1) determine the behavioral and endocrine outcomes of chronic social stress and their persistence or reversibility by antidepressant drug treatment; 2) test whether social stress results in depressive-like behaviors through epigenetic modifications; and 3) validate and extend top DNAm difference findings through study of gene expression, DNAm in other brain regions, DNAm in blood, and histone modifications in genes. PUBLIC HEALTH RELEVANCE: We propose to determine the epigenetic contribution to major depressive disorder (MDD), the most common debilitating psychiatric disorder, through a highly focused approach that combines cutting-edge epigenomic analysis with a mouse model of stress-induced depression. MDD is among the world's most important public health problems, as it is the fourth leading cause of disability globally and projected to rise to second by 2020. By identifying genomic locations where stress changes DNA methylation in the brain, we hope to glean fundamental new insights into the pathogenesis of depression and thus advance the effort to improve treatments for this illness.