Epigenetic Studies in Suicide Brain

描述（由申请人提供）：自杀是一个主要的公共卫生问题。尽管人们已经尝试研究自杀的神经生物学，但与这种疾病相关的精确分子机制仍不清楚。有人提出，情绪障碍/自杀是由于大脑无法对环境刺激做出适当的适应性反应。表观基因组过程不仅对正常细胞发育和分化至关重要，而且对通过非致突变机制调节基因功能也至关重要。DNA甲基化是通过改变启动子调控序列来调节基因-环境相互作用的主要表观遗传学方法，并与大脑功能的稳定和适应性变化有关。在我们之前的研究中，我们一致表明自杀者死后大脑中涉及神经和结构可塑性的基因表达显著下调，这表明基因表达的改变可能在自杀的病因学中至关重要。有趣的是，大量基因在甲基化程度和基因表达量之间表现出负相关关系。因此，不能排除DNA的表观遗传修饰导致自杀者大脑中某些基因表达改变的可能性。事实上，在基因表达的表观基因组调控领域的研究已经提出了一种假设，即复杂精神疾病的多基因性质可能表明，通过表观基因组机制，一个共同的途径参与了多个基因的失调。尽管仍处于婴儿期，但最近的证据表明，表观遗传因素可能在精神疾病的致病机制中发挥关键作用。为了研究DNA的表观遗传修饰是否在自杀行为中起任何作用，我们提出了一项初步研究，对包括抑郁自杀、非自杀抑郁和匹配良好的非精神健康正常对照受试者的前额叶皮层进行大规模表观遗传分析。更具体地说，我们将研究以下内容：1)所有已知蛋白质编码基因启动子的DNA甲基化模式；2)利用亚硫酸氢钠修饰对CpG位点的metC/CAEC/T比值进行定位，确认微阵列结果；3)采用基于网络的方法测试表观基因组数据的模块化；4)表观基因组图谱与全球基因表达数据的结合分析。为了进一步复制DNA甲基化研究，在另一组抑郁症自杀和健康对照受试者中，我们建议随访10到15个基因启动子，这些基因在抑郁症自杀和正常对照受试者之间表现出最大的表观基因组差异。据我们所知，这项拟议中的研究将是此类自杀研究中的首例，并可能确定自杀大脑中的主要表观遗传修饰。提出的研究也将为我们未来的表观遗传学研究铺平道路，并将对确定自杀的病因学和致病机制至关重要。

DESCRIPTION (provided by applicant): Suicide is a major public health concern. Although attempts have been made to investigate the neurobiology of suicide, the precise molecular mechanisms associated with this disorder are still unclear. It has been proposed that mood disorders/suicide result from an inability of the brain to make appropriate adaptive responses to environmental stimuli. Epigenomic processes are essential not only for normal cellular development and differentiation, but also critical for regulation of gene function through non-mutagenic mechanisms. DNA methylation is the major epigenetic approach for modulating the gene-environment interaction through alterations of promoter regulatory sequences and is associated with stable and adaptive changes in brain functions. In our previous studies, we have consistently shown that the expression of genes involved in neural and structural plasticity is significantly down-regulated in the postmortem brain of suicide subjects, suggesting that altered gene expression may be crucial in the etiology of suicide. Interestingly, a large number of genes exhibit an inverse correlation between the degree of methylation and the magnitude of gene expression. Therefore, the possibility that epigenetic modifications of DNA causing such alterations in the expression of certain genes in brain of suicide subjects, cannot be ruled out. In fact, research in the area of epigenomic regulation of gene expression has led to the hypothesis that the polygenic nature of complex psychiatric disorders might indicate that a common pathway is involved in the dysregulation of multiple genes through an epigenomic mechanism. Although still in infancy, recent evidence suggests that epigenetic factors may play a key role in the pathogenic mechanisms of psychiatric illnesses. To investigate whether epigenetic modifications of DNA play any role in suicidal behavior, we are proposing a pilot study to investigate large- scale epigenetic profiling in the prefrontal cortex of a cohort comprising depressed suicide, non-suicide depressed and well-matched non-psychiatric healthy normal comparison subjects. More specifically, we will examine the following: 1) DNA methylation pattern at the promoters of all known protein-coding genes; 2) confirm microarray results using sodium bisulfite modification-based mapping of metC/CAEC/T ratios in the CpG sites; 3) use a network-based approach to test the modularity of the epigenomic data; and 4) combined analysis of epigenomic profiles and global gene expression data. To further replicate the DNA methylation study, in another cohort of depressed suicide and healthy comparison subjects, we propose to follow-up 10 to 15 promoters of genes that exhibit the largest epigenomic differences between depressed suicide and normal control subjects. To our knowledge, the proposed research will be the first of its kind in suicide research, and will likely identify major epigenetic modifications in the suicide brain. The proposed studies will also pave the way for our future epigenetic studies and will be crucial for identifying the etiological and pathogenic mechanisms of suicide. PUBLIC HEALTH RELEVANCE: Our proposed study will yield important information on the neurobiology of suicide, which may eventually lead to better treatment and possibly prevention of suicide.