Characterizing Life-Span Sociobehavioral Determinants of DNA (Hydroxy)Methylation

表征 DNA（羟基）甲基化的寿命社会行为决定因素

• 批准号: 8767346
• 负责人: Jun Dai
• 金额: $ 22.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767346
• 关键词: Address; Affect; Age; Aggressive behavior; Aging; Alcohol consumption; Anxiety; Area; Behavior; Biochemical; Biological; Cardiovascular system; Cause of Death; Cessation of life; Clinical; Controlled Study; Cytosine; DNA; DNA Methylation; Data; Decision Making; Development; Diet; Disease; Dizygotic Twins; Eating; Environment; Environmental Risk Factor; Epidemiologic Studies; Epigenetic Process; Family history of; Future; Gene Expression; General Population; Genes; Genetic; Genome; Genomics; Individual; Inherited; Interview; Life; Life Expectancy; Life Style; Live Birth; Longevity; Measures; Methodology; Methylation; Modification; Monozygotic Twinning; Monozygotic twins; Mus; National Heart, Lung, and Blood Institute; Observational Study; Outcome; Parents; Persons; Physical Examination; Physical activity; Pilot Projects; Preparation; Preventive; Process; Publishing; Regimen; Research; Resources; Sampling; Schools; Smoking Behavior; Social Behavior; Staging; Techniques; Therapeutic; Twin Multiple Birth; Twin Studies; Vital Status; Work; acquired factor; cohort; density; design; environmental change; genome wide association study; genome-wide; innovation; male; next generation sequencing; novel; psychologic; public health relevance; seal

DESCRIPTION (provided by applicant): The 5-methylated cytosine (5mC) turns off gene expression and the 5-hydroxymethylated cytosine (5hmC) turns it on. Both epigenetic modifications are thought to be one mechanism through which sociobehavioral factors regulate gene expression. However, the lab technique used in previous studies of DNA methylation related to sociobehavioral factors cannot distinguish 5mC from 5hmC and has other limitations. There is not any published study of 5hmC related to sociobehavioral factors. To date, the sociobehavioral determinants of DNA (hydroxy) methylation are largely unknown. Genetic factors can affect epigenetic modifications. Twins are genetically informative. Co-twins of a twin pair share germline genomic sequence [monozygotic twins (MZ) share 100% while dizygotic twins (DZ) on average share 50%)], germline epigenetic modifications inherited from parents, and common environment (i.e. environmental factors shared between co-twins, including age-cohort-period effects, family history of disease, maternal and other familial influences, sample processing and storage conditions). These shared factors can be uniquely controlled for in the co-twin study through comparing co-twins with each other, but not in a traditional epidemiologic study. In the NHLBI Twin Study, through physical examinations and in- person interviews, detailed data were collected on environmental factors from different aging stages, including sociobehavioral, psychological, dietary, lifestyle, biochemical, and clinical factors at exams 1 to 5 (1969-2000); data on vital status, cause of death, and age at death were collected through Dec 31, 2010; and buffy coat DNA samples were collected at age 60-74 years [exam 3 (1986-87)]. We have developed novel lab techniques that overcome the technical limitations mentioned above and can specifically measure both 5mC and 5hmC. Thus, by use of existing resources in the NHLBI Twin Study and the novel lab technique we have developed, we propose a co-twin study of the life-span sociobehavioral determinants of systemic DNA (hydroxy) methylation separated from genetic confounding. Our long-term research objective is to understand the interaction of sociobehavioral factors with the genome through epigenetic modifications and resultant disease consequences and the longevity, independent of the germline. In this R21 project, we will include a representative sample of 20 MZ and 20 DZ male twin pairs discordant for cardiovascular death and age at death from the NHLBI Twin Study of white male twins. These twins were born between 1917 and 1927, a period when 2 male MZ pairs and 4 male DZ pairs of twins were born per 1,000 live births. The specific aims of this R21 project are: 1) to measure genome-wide 5mC and 5hmC with our novel lab techniques, 2) to identify differentially 5-methylated genomic regions (DMRs) and 5- hydroxymethylated genomic regions (DhMRs), and 3) to explore sociobehavioral determinants of DMRs and DhMRs across the lifespan with life-span sociobehavioral data at exam 1. We aim to generate preliminary data for the future, large-scale study as stated in RFA-TW-13-002. The significance of our study lies in the development of sociobehavioral regimen to prolong the life expectancy.

描述(申请人提供)：5-甲基胞嘧啶(5mC)关闭基因表达，5-羟甲基胞嘧啶(5hmC)启动基因表达。这两种表观遗传修饰都被认为是社会行为因素调节基因表达的一种机制。然而，在之前与社会行为因素相关的DNA甲基化研究中使用的实验室技术不能区分5mC和5hmC，并且有其他局限性。目前还没有关于5HmC与社会行为因素相关的研究发表。到目前为止，DNA(羟基)甲基化的社会行为决定因素在很大程度上是未知的。遗传因素可以影响表观遗传修饰。双胞胎具有遗传信息性。一对双胞胎的同卵双胞胎共享种系基因组序列[同卵双胞胎(MZ)共享100%，异卵双胞胎(DZ)平均共享50%)]，从父母那里继承的种系表观遗传修改，以及共同的环境因素(即同卵双胞胎之间共享的环境因素，包括年龄队列时期的影响、家族疾病史、母亲和其他家庭影响、样本处理和保存条件)。这些共同的因素可以在同卵双胞胎研究中通过比较同卵双胞胎彼此来唯一地控制，而不是在传统的流行病学研究中。在NHLBI双胞胎研究中，通过体检和面谈，收集了来自不同老龄化阶段的环境因素的详细数据，包括测试1至2的社会行为、心理、饮食、生活方式、生化和临床因素 收集了截至2010年12月31日的生命状况、死因和死亡年龄的数据；收集了60-74岁的巴菲毛皮DNA样本[检查3(1986-87)]。我们开发了新的实验室技术，克服了上面提到的技术限制，可以专门测量5mC和5hmC。因此，通过利用NHLBI双胞胎研究中的现有资源和我们开发的新的实验室技术，我们提出了一项从遗传混杂中分离出来的系统DNA(羟基)甲基化的终身社会行为决定因素的共同研究。我们的长期研究目标是了解社会行为因素通过表观遗传修饰和由此产生的疾病后果与基因组的相互作用，以及不受生殖系影响的寿命。在这个R21项目中，我们将包括NHLBI对白人男性双胞胎研究中与心血管死亡和死亡年龄不一致的20 MZ和20 DZ男性双胞胎的代表性样本。这对双胞胎出生于1917年至1927年，当时每1000名活产婴儿中就有2对男性MZ双胞胎和4对男性DZ双胞胎出生。这个R21项目的具体目标是：1)用我们新的实验室技术测量全基因组的5mC和5hmC，2)识别不同的5-甲基化基因组区(DMRS)和5-羟甲基化基因组区(DMRS)，以及3)利用试验1的寿命社会行为数据探索DMRS和DMRS的社会行为决定因素。我们的目标是为未来的大规模研究产生初步数据，如RFA-TW-13-002所述。我们研究的意义在于开发社会行为养生方法来延长预期寿命。