成人表观遗传时钟点的发育动态特征。

IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Rosa H Mulder, Alexander Neumann, Janine F Felix, Matthew Suderman, Charlotte A M Cecil
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引用次数: 0

摘要

背景:DNA甲基化(DNAm)是一种表观遗传机制,它能调节基因活动以应对遗传和环境影响。基因组特定位点上的 DNAm 可用来计算 "表观遗传时钟",这是年龄和老化的有力生物标志。然而,人们对这些时钟位点在发育过程中的 "行为 "以及哪些因素会影响它们在生命早期的变化知之甚少。这些知识可用于在与年龄有关的疾病发生之前优化健康老龄化:我们利用两个基于人群的纵向队列(N = 5019 个样本,来自 2348 个个体)的结果来描述成人时钟点从出生到成年早期的轨迹。为了探索哪些因素可能会导致这些时钟点的早期个体差异,我们还根据现有的全表观基因组关联荟萃分析,检测了遗传因素和产前暴露的富集性:我们发现,时钟位点(i)在发育轨迹上存在很大差异,往往随着时间的推移呈现非线性变化;(ii)与非时钟位点相比,个体之间从出生起就存在差异的可能性要大得多,这种差异可预测以后年龄段的 DNAm 变异;(iii)受遗传影响和产前环境暴露(包括产前吸烟、饮食和母体身体健康状况)的富集:这些结果表明,与年龄有关的表观遗传过程可能起源于发育早期,而且在个体之间存在差异。了解这些差异的驱动因素有助于我们制定更好的战略,促进健康老龄化:这项研究是在C.A.M.C.担任Hevolution/AFAR老龄生物学和老年科学研究新研究员奖获得者期间进行的。个人资助详情以及团队资助详情可参见致谢。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Characterising developmental dynamics of adult epigenetic clock sites.

Background: DNA methylation (DNAm), an epigenetic mechanism that regulates gene activity in response to genetic and environmental influences, changes as we age. DNAm at specific sites on the genome can be used to calculate 'epigenetic clocks', which are powerful biomarkers of age, as well as of ageing. However, little is known about how these clock sites 'behave' during development and what factors influence their variability in early life. This knowledge could be used to optimise healthy ageing well before the onset of age-related conditions.

Methods: We leveraged results from two longitudinal population-based cohorts (N = 5019 samples from 2348 individuals) to characterise trajectories of adult clock sites from birth to early adulthood. To explore what factors may drive early individual differences at these clock sites, we also tested for enrichment of genetic factors and prenatal exposures based on existing epigenome-wide association meta-analyses.

Findings: We find that clock sites (i) diverge widely in their developmental trajectories, often showing non-linear change over time; (ii) are substantially more likely than non-clock sites to vary between individuals already from birth, differences that are predictive of DNAm variation at later ages; and (iii) show enrichment for genetic influences and prenatal environmental exposures, including prenatal smoking, diet and maternal physical health conditions.

Interpretation: These results suggests that age(ing)-related epigenetic processes might originate-and differ between individuals-already very early in development. Understanding what drives these differences may in future help us to devise better strategies to promote healthy ageing.

Funding: This research was conducted while C.A.M.C. was a Hevolution/AFAR New Investigator Awardee in Aging Biology and Geroscience Research. Full personal funding details, as well as cohort funding details, can be found in the Acknowledgements.

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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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