A comprehensive map of the aging blood methylome in humans

IF 10.1 1区生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Genome Biology Pub Date : 2024-09-06 DOI:10.1186/s13059-024-03381-w

Kirsten Seale, Andrew Teschendorff, Alexander P. Reiner, Sarah Voisin, Nir Eynon

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Abstract

During aging, the human methylome undergoes both differential and variable shifts, accompanied by increased entropy. The distinction between variably methylated positions (VMPs) and differentially methylated positions (DMPs), their contribution to epigenetic age, and the role of cell type heterogeneity remain unclear. We conduct a comprehensive analysis of > 32,000 human blood methylomes from 56 datasets (age range = 6–101 years). We find a significant proportion of the blood methylome that is differentially methylated with age (48% DMPs; FDR < 0.005) and variably methylated with age (37% VMPs; FDR < 0.005), with considerable overlap between the two groups (59% of DMPs are VMPs). Bivalent and Polycomb regions become increasingly methylated and divergent between individuals, while quiescent regions lose methylation more uniformly. Both chronological and biological clocks, but not pace-of-aging clocks, show a strong enrichment for CpGs undergoing both mean and variance changes during aging. The accumulation of DMPs shifting towards a methylation fraction of 50% drives the increase in entropy, smoothening the epigenetic landscape. However, approximately a quarter of DMPs exhibit anti-entropic effects, opposing this direction of change. While changes in cell type composition minimally affect DMPs, VMPs and entropy measurements are moderately sensitive to such alterations. This study represents the largest investigation to date of genome-wide DNA methylation changes and aging in a single tissue, providing valuable insights into primary molecular changes relevant to chronological and biological aging.

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人类老化血液甲基组综合图谱

在衰老过程中，人类甲基组会发生不同和可变的变化，同时伴随着熵的增加。可变甲基化位置（VMPs）和差异甲基化位置（DMPs）之间的区别、它们对表观遗传年龄的贡献以及细胞类型异质性的作用仍不清楚。我们对来自 56 个数据集（年龄范围 = 6-101 岁）的 > 32,000 个人类血液甲基组进行了全面分析。我们发现血液甲基组中有很大一部分随年龄发生差异甲基化（48% DMPs；FDR < 0.005）和随年龄发生变异甲基化（37% VMPs；FDR < 0.005），两组之间有相当大的重叠（59% 的 DMPs 是 VMPs）。二价区和多聚核糖区的甲基化程度越来越高，个体间的差异也越来越大，而静止区的甲基化损失则更为均匀。在衰老过程中，计时时钟和生物钟（而非衰老时钟）都显示出平均值和方差变化的 CpGs 有很强的富集性。DMPs 的积累趋向于甲基化比例达到 50%，从而推动了熵的增加，使表观遗传景观更加平滑。然而，大约四分之一的 DMPs 表现出反熵效应，与这一变化方向相反。细胞类型组成的变化对 DMPs 的影响很小，而 VMPs 和熵的测量对这种变化的敏感度则适中。这项研究是迄今为止对单一组织中全基因组 DNA 甲基化变化和衰老的最大规模调查，为了解与时间和生物衰老相关的主要分子变化提供了宝贵的信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Genome Biology Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

21.00

自引率

3.30%

发文量

241

审稿时长

2 months

期刊介绍： Genome Biology stands as a premier platform for exceptional research across all domains of biology and biomedicine, explored through a genomic and post-genomic lens. With an impressive impact factor of 12.3 (2022),* the journal secures its position as the 3rd-ranked research journal in the Genetics and Heredity category and the 2nd-ranked research journal in the Biotechnology and Applied Microbiology category by Thomson Reuters. Notably, Genome Biology holds the distinction of being the highest-ranked open-access journal in this category. Our dedicated team of highly trained in-house Editors collaborates closely with our esteemed Editorial Board of international experts, ensuring the journal remains on the forefront of scientific advances and community standards. Regular engagement with researchers at conferences and institute visits underscores our commitment to staying abreast of the latest developments in the field.