无活性的X染色体随着年龄的增长积累了广泛的表观遗传变异。

IF 5.7 2区 医学 Q1 Medicine
Yunfeng Liu, Lucy Sinke, Thomas H Jonkman, Roderick C Slieker, Erik W van Zwet, Lucia Daxinger, Bastiaan T Heijmans
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引用次数: 2

摘要

背景:表观遗传控制的丧失是衰老的标志。表观遗传机制中最突出的作用是通过DNA甲基化使雌性X染色体的两个拷贝中的一个失活。因此,年龄相关的x染色体失活(XCI)的破坏可能有助于女性的衰老过程。方法:利用Illumina 450k甲基化阵列(Illumina 450k methylation array)对2343名女性和1688名男性的全血样本中X染色体上的9777个CpGs进行分析,并使用一个全血和一个纯化单核细胞数据集(共991/924名女性/男性)重复分析结果。我们使用双广义线性模型检测年龄相关的差异甲基化CpGs (aDMCs),其平均甲基化水平随年龄而变化,以及年龄相关的可变甲基化CpGs (aVMCs),其甲基化水平随年龄变化更大。结果:在女性中,admc相对不常见(n = 33),并且优先发生在已知逃避XCI的区域。相比之下,许多cpg (n = 987)显示出随年龄增加的方差(avmc)。值得注意的是,avmc在纯化单核细胞中的复制率也很高(94%),表明细胞组成的独立性。avmc在CpG岛和受XCI影响的区域积累,表明它们起源于失活的X染色体。在雄性中,仅携带一条X染色体的活跃拷贝,admc (n = 316)主要由细胞组成驱动,而avmc复制良好(95%),但不常见(n = 37)。结论:我们的研究结果表明,非活性X染色体上与年龄相关的DNA甲基化差异主要是由变异性的积累引起的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The inactive X chromosome accumulates widespread epigenetic variability with age.

The inactive X chromosome accumulates widespread epigenetic variability with age.

The inactive X chromosome accumulates widespread epigenetic variability with age.

The inactive X chromosome accumulates widespread epigenetic variability with age.

Background: Loss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the aging process in women.

Methods: We analyzed 9,777 CpGs on the X chromosome in whole blood samples from 2343 females and 1688 males (Illumina 450k methylation array) and replicated findings in duplicate using one whole blood and one purified monocyte data set (in total, 991/924 females/males). We used double generalized linear models to detect age-related differentially methylated CpGs (aDMCs), whose mean methylation level differs with age, and age-related variably methylated CpGs (aVMCs), whose methylation level becomes more variable with age.

Results: In females, aDMCs were relatively uncommon (n = 33) and preferentially occurred in regions known to escape XCI. In contrast, many CpGs (n = 987) were found to display an increased variance with age (aVMCs). Of note, the replication rate of aVMCs was also high in purified monocytes (94%), indicating an independence of cell composition. aVMCs accumulated in CpG islands and regions subject to XCI suggesting that they stemmed from the inactive X. In males, carrying an active copy of the X chromosome only, aDMCs (n = 316) were primarily driven by cell composition, while aVMCs replicated well (95%) but were infrequent (n = 37).

Conclusions: Our results imply that age-related DNA methylation differences at the inactive X chromosome are dominated by the accumulation of variability.

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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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