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

描述(由申请人提供)：我们建议通过一种高度集中的方法，结合尖端的表观基因组分析和基于压力的小鼠疾病模型，确定表观遗传学对抑郁症的贡献，抑郁症是最常见的衰弱精神障碍。众所周知，应激在引发严重抑郁障碍(MDD)中发挥着重要作用，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，压力介导的表观遗传控制BDNF，一个在抑郁和抗抑郁反应中起关键作用的基因，提供了表观遗传机制可以中介这种相互作用的分子证据。约翰斯·霍普金斯大学的一位联合调查员最近的另一项研究表明，包括BDNF在内的基因的DNA去甲基化在神经可塑性和神经发生中发挥作用，以响应电惊厥刺激。这些结果表明，从全基因组表观遗传学的方法研究应激诱导和药物逆转的啮齿动物脑DNA变化中，可以收集到对抑郁症的病因和病理生理学以及治疗反应机制的新见解。执行全基因组表观遗传学研究的工具刚刚问世，我们位于约翰霍普金斯大学的表观遗传学中心在开发此类工具方面一直处于领先地位，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(CHALM)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对其成功至关重要的方面拥有专业知识，包括压力的啮齿动物模型、抑郁症的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，确定慢性社会应激的行为和内分泌结果及其持久性或可逆性；2)测试社会应激是否通过表观遗传修饰导致抑郁样行为；以及3)通过研究基因表达、其他脑区的dNaM、血液中的dNaM和基因中的组蛋白修饰来验证和扩大最大的dNaM差异发现。 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的小鼠模型相结合，确定表观遗传学对严重抑郁障碍(MDD)的贡献，MDD是最常见的衰弱精神障碍。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致残原因，预计到2020年将上升到第二位。通过确定应激改变大脑DNA甲基化的基因组位置，我们希望收集对抑郁症发病机制的基本新见解，从而推动改进这种疾病的治疗。

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.