中国健康长寿人群基因组DNA甲基化修饰模式及其功能作用研究

The health situation of elderly people in China raises great challenges and new requirements for the study of aging and age-related diseases. Centenarians, as an exceptional model of healthy aging, not only have much longer lifespan, but also exhibit the ability in delaying or escaping from some serious age-associated diseases, suggesting the existence of protective factors in these people. Therefore, investigating the genetic protective factors in the centenarians and understanding their molecular mechanism in regulating healthy aging will provide novel insights and new opportunity for prevention and therapy of aging diseases. We previously obtained and analyzed 171 transcriptomes of peripheral blood samples from centenarian families (consisting of centenarian, F1 offspring and spouses of the F1 offspring). Our results show that the centenarians display a unique gene expression pattern and it can be partially inherited to their offspring. However, it remains unclear how the centenarians possess the specific gene expression model and what is the inheritable strategy. Given the fact that DNA methylation is inheritable and also an important regulator in gene expression, we therefore plan to screen their DNA methylome information of the same batch of longevity population. By establishing the specific DNA methylation pattern in the longevity samples, combining with their transcriptome information, and complementing the functional validation of additional longevity populations from multi-regions of China, we hope to uncover the core methylation sites that are able to regulate the gene (especially the genes associated with age-related diseases) expression. This project will not only help to better understand the mechanisms on healthy aging and finding out new epigenetic protective factors, but also provide new pathways and new targets for exploring novel intervention strategies in delaying senescence.

作为健康衰老典范的百岁老人，寿命超长且能规避重大老年疾病的困扰，开展其健康衰老机制研究，将可能为老年病的防治提供新的视角和办法。我们前期采集并分析了171例中国海南百岁老人家系样本的转录组信息，结果发现：长寿人群确实存在独特的基因差异表达模式，且该模式可部分遗传给F1代，但调控机制不明。鉴于DNA甲基化修饰可遗传且是基因表达的重要调控因子，我们推测DNA甲基化修饰很可能调控了长寿人群特异基因表达模式并介导其（部分）遗传给后代。本项目拟对同一批已测定RNA-seq的长寿家系样本，采用甲基化芯片扫描等手段获得其甲基化图谱并构建长寿人群特有DNA甲基化修饰模式；结合其基因表达数据，辅之以多地区长寿样本扫描验证及功能研究，旨在揭示影响健康衰老及/或调控老年病相关基因表达的核心甲基化位点及其功能作用。项目的开展有助于揭示可能存在的健康长寿表观遗传保护因子，为探索老年病的防治策略提供新的线索和证据。

作为健康衰老典范的百岁老人，寿命超长且能规避重大老年疾病的困扰，开展其健康衰老机制研究，将可能为老年病的防治提供新的视角和办法。本项目利用全基因组甲基化测序技术成功获取中国海南省百岁老人家系135例外周血样本单碱基分辨率DNA甲基化组数据。通过百岁老人和百岁F1后代配偶（作为一般对照样本）的数据比较分析，我们鉴定出约25万个百岁老人显著差异甲基化位点，其中部分（21%）位点在百岁F1后代中存在同样的甲基化差异模式。重点是，我们发现百岁老人差异甲基化位点在基因组上存在一定的聚集性（非随机分布）。在此，我们一共甄别到1232个百岁老人高甲基化位点聚集区域（甲基化峰）和5224个低甲基化位点聚集区域（甲基化谷）。信息学分析发现这些区域远离转录起始位点：高甲基化区域富集于增强子；低甲基化区域富集于绝缘子。基于样本匹配的DNA甲基化组-转录组联合分析，我们发现这些区域潜在调控的基因主要富集于免疫、Wnt、脂代谢等衰老、老年性疾病密切相关的生物学过程，提示百岁老人特异DNA甲基化模式在人类健康老化中起到重要的作用。综上所述，本项目甄别到参与调控健康衰老及/或调控老年病相关基因表达的核心甲基化区域（位点），为探索老年病的防治策略提供了新的线索和证据。