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确定抑郁症（最常见的衰弱性精神疾病）的表观遗传贡献，该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。众所周知，压力在引发重度抑郁症（MDD）中起着重要作用，可能是通过与遗传易感性因素的相互作用。最近的工作表明，压力介导的BDNF（一种在抑郁症和抗抑郁反应中起关键作用的基因）的表观遗传控制，提供了表观遗传机制可以介导这种相互作用的分子证据。约翰霍普金斯的一位合作研究者最近的其他工作表明，包括BDNF在内的基因的DNA去甲基化在响应电惊厥刺激的神经可塑性和神经发生中起作用。这些结果表明，抑郁症的病因学和病理生理学的新见解，以及治疗反应的机制，可以从全基因组表观遗传学的方法来研究应激诱导的，药物逆转，啮齿动物脑DNA的变化收集的可能性。进行全基因组表观遗传学研究的工具刚刚问世，我们的约翰霍普金斯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。除了我们的表观基因组学专业知识外，我们的团队还在该项目的其他方面拥有专业知识，这些方面对其成功至关重要，包括啮齿动物压力模型，抑郁症遗传学和神经生物学。本研究的主要目的是：1）确定慢性社会应激对行为和内分泌的影响以及抗抑郁药物治疗的持久性或可逆性; 2）检测社会应激是否通过表观遗传修饰导致抑郁样行为;和3）通过研究基因表达、其他脑区域中的DNAm、血液中的DNAm和基因中的组蛋白修饰。 公共卫生相关性：我们建议通过一种高度集中的方法，将尖端的表观基因组分析与应激诱导抑郁症的小鼠模型相结合，来确定重性抑郁症（MDD）的表观遗传贡献，MDD是最常见的使人衰弱的精神疾病。MDD是世界上最重要的公共卫生问题之一，因为它是全球第四大残疾原因，预计到2020年将上升到第二位。通过确定压力改变大脑中DNA甲基化的基因组位置，我们希望收集有关抑郁症发病机制的基本新见解，从而推动改善这种疾病治疗的努力。

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.