Epigenetic responses to social and environmental cues in early life and over the life course: impact on healthy ageing in UK population-based cohorts

生命早期和整个生命过程中对社会和环境线索的表观遗传反应：对英国人口群体健康老龄化的影响

• 批准号: ES/N000404/1
• 负责人: Jordana Bell
• 金额: $ 63.97万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=ES%2FN000404%2F1
• 关键词: Epigenetic; responses; social; environmental; cues

Epigenetic mechanisms such as DNA methylation are key regulators of gene function. Epigenetic signals are malleable and can change in response to internal and external stimuli. The epigenome thereby provides a mechanism of interaction between the genome with the environment, and we hypothesize that early life stimuli and exposures over the life course leave an epigenetic mark.The proposal will explore DNA methylation in 4,024 samples from four British cohort studies (the MRC National Survey for Health and Development (NSHD) or 1946 birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK)) in order to identify epigenetic signatures of early life experience and exposure to social, environmental, and biological stimuli over the life course, linking findings to changes in physical and cognitive function during ageing. Each study captures a range of early life experiences, longitudinal health measures and lifestyle questionnaire data from adult life, DNA samples collected at single or multiple time-points, and in a sample subset, multiple genomic data for follow-up analyses. The primary research design is a prospective analysis of longitudinal data across 2,336 blood and 1,688 buccal samples from the four cohorts. The first aim of the research will be to establish whether biological, environmental, and social stimuli in early life and over the life course result in detectable differences in DNA methylation profiles in adults. We will consider whether there are epigenetic associations with a number of factors including biological, environmental and social factors in utero and in early childhood (e.g. birthweight, childhood growth, maternal smoking during pregnancy, nutrition, parental socioeconomic position), and in later life: (e.g. smoking, alcohol consumption, physical activity, diet, stressful events, adult socioeconomic position). The second aim is to assess whether there are differences between cohorts in DNA methylation patterns, comparing samples containing individuals born in different years (1946, 1958 and 1970), accounting for age, since these may reflect differences between cohorts in environmental and social influences in early life. Our third aim is to explore the role of epigenetics in healthy functional ageing by applying a two-fold approach. First, we will compare epigenetic signatures to longitudinal functional health trajectories throughout life across cohorts, across cell types (blood and buccal), and across different age categories. We will explore whether DNA methylation signatures of early life experiences can mediate functional ageing trajectories (such as cardiovascular, lung and cognitive function), and whether they can be reversed in response to social and environmental exposures in later life. Our fourth aim is to apply a new approach to estimate biological age, the epigenetic clock, to assess the rate of epigenetic ageing and relate it to early life stimuli and longitudinal biomedical, social, and environmental trajectories. Additional analyses in subsamples will include DNA methylation profiling at multiple time-points to estimate reversibility of DNA methylation, cross-tissue comparison across blood, buccal, and additional tissues, and gene expression analysis for functional interpretation. Replication will be pursued in 3,970 samples from four independent UK-population-based cohorts.The findings will establish the feasibility of our approach by combining modest samples of participants across each of the four cohorts into a large sample well powered to determine the influence of early life factors on epigenetic signatures throughout the life course. The proof of concept approach will allow such analyses to be extended to larger samples within cohorts by forming the basis for further funding applications and establishing an epigenetic research network across UK population-based cohorts.

表观遗传机制，如DNA甲基化，是基因功能的关键调节因素。表观遗传信号是可塑性的，可以随着内部和外部刺激的反应而改变。因此，表观基因组提供了一种基因组与环境相互作用的机制，我们假设早期生活刺激和生命过程中的暴露会留下表观遗传标记。该提案将探索来自四项英国队列研究(MRC国家健康与发展调查(NSHD)或1946出生队列、国家儿童发展研究(NCDS)或1958出生队列、1970年英国队列研究(BCS70)和TwinsUK队列(TwinsUK))的4,024个样本中的DNA甲基化，以确定早期生活经历和在生命过程中暴露于社会、环境和生物刺激的表观遗传学特征，将发现与衰老期间身体和认知功能的变化联系起来。每项研究都收集了成人生活中的一系列早期生活经历、纵向健康测量和生活方式问卷数据、在单个或多个时间点收集的DNA样本，以及在一个样本子集中用于后续分析的多个基因组数据。主要的研究设计是对来自四个队列的2336份血液和1688份口腔样本的纵向数据进行前瞻性分析。这项研究的第一个目标将是确定早期生命和整个生命过程中的生物、环境和社会刺激是否会导致成年人DNA甲基化图谱的可检测到的差异。我们将考虑表观遗传学是否与一些因素有关，包括子宫内和儿童早期的生物、环境和社会因素(例如出生体重、儿童生长、母亲在怀孕期间吸烟、营养、父母的社会经济地位)，以及在以后的生活中：(例如吸烟、饮酒、体育活动、饮食、应激事件、成人社会经济地位)。第二个目的是评估不同群体之间DNA甲基化模式是否存在差异，比较包含出生在不同年份(1946年、1958年和1970年)的个体的样本，考虑年龄，因为这些样本可能反映出群体之间在早期生活中环境和社会影响方面的差异。我们的第三个目标是通过应用两种方法来探索表观遗传学在健康功能性衰老中的作用。首先，我们将比较表观遗传特征与跨队列、跨细胞类型(血液和口腔)以及跨不同年龄类别的生命周期的纵向功能健康轨迹。我们将探索早期生活经历的DNA甲基化特征是否可以调节功能性衰老轨迹(如心血管、肺和认知功能)，以及它们是否可以在以后的生活中因社会和环境暴露而逆转。我们的第四个目标是应用一种新的方法来估计生物年龄，即表观遗传时钟，评估表观遗传衰老的速度，并将其与早期生命刺激和纵向生物医学、社会和环境轨迹联系起来。子样本中的其他分析将包括在多个时间点进行DNA甲基化分析以评估DNA甲基化的可逆性，跨组织比较血液、口腔和其他组织，以及用于功能解释的基因表达分析。我们将对来自四个独立的英国人群队列的3970个样本进行复制。这些发现将确定我们方法的可行性，方法是将四个队列中每个队列的参与者的适度样本组合成一个大样本，以确定早期生命因素对整个生命过程中表观遗传特征的影响。概念验证方法将通过形成进一步资助申请的基础，并在基于英国人口的队列中建立表观遗传学研究网络，使此类分析能够扩展到队列中的更大样本。

项目成果

Novel regional age-associated DNA methylation changes within human common disease-associated loci.

• DOI: 10.1186/s13059-016-1051-8
• 发表时间: 2016-09-23
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Bell CG;Xia Y;Yuan W;Gao F;Ward K;Roos L;Mangino M;Hysi PG;Bell J;Wang J;Spector TD
• 通讯作者: Spector TD

Additional file 1: of DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation

附加文件1：体外受精双胞胎的不孕基因DNA甲基化变化

• DOI: 10.6084/m9.figshare.c.3726244_d1
• 发表时间: 2017
• 作者: Castillo-Fernandez J

DNA methylation-based measures of biological age: meta-analysis predicting time to death.

• DOI: 10.18632/aging.101020
• 发表时间: 2016-09-28
• 期刊: Aging
• 作者: Chen BH;Marioni RE;Colicino E;Peters MJ;Ward-Caviness CK;Tsai PC;Roetker NS;Just AC;Demerath EW;Guan W;Bressler J;Fornage M;Studenski S;Vandiver AR;Moore AZ;Tanaka T;Kiel DP;Liang L;Vokonas P;Schwartz J;Lunetta KL;Murabito JM;Bandinelli S;Hernandez DG;Melzer D;Nalls M;Pilling LC;Price TR;Singleton AB;Gieger C;Holle R;Kretschmer A;Kronenberg F;Kunze S;Linseisen J;Meisinger C;Rathmann W;Waldenberger M;Visscher PM;Shah S;Wray NR;McRae AF;Franco OH;Hofman A;Uitterlinden AG;Absher D;Assimes T;Levine ME;Lu AT;Tsao PS;Hou L;Manson JE;Carty CL;LaCroix AZ;Reiner AP;Spector TD;Feinberg AP;Levy D;Baccarelli A;van Meurs J;Bell JT;Peters A;Deary IJ;Pankow JS;Ferrucci L;Horvath S
• 通讯作者: Horvath S

Blood DNA methylation sites predict death risk in a longitudinal study of 12,300 individuals

• DOI: 10.18632/aging.103408
• 发表时间: 2020-07-31
• 期刊: AGING-US
• 影响因子: 5.2
• 作者: Colicino, Elena;Marioni, Riccardo;Baccarelli, Andrea
• 通讯作者: Baccarelli, Andrea

Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects.

• DOI: 10.1186/s13148-021-01018-4
• 发表时间: 2021-02-16
• 期刊: Clinical epigenetics
• 影响因子: 5.7
• 作者: Christiansen C;Castillo-Fernandez JE;Domingo-Relloso A;Zhao W;El-Sayed Moustafa JS;Tsai PC;Maddock J;Haack K;Cole SA;Kardia SLR;Molokhia M;Suderman M;Power C;Relton C;Wong A;Kuh D;Goodman A;Small KS;Smith JA;Tellez-Plaza M;Navas-Acien A;Ploubidis GB;Hardy R;Bell JT
• 通讯作者: Bell JT