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Human non-CpG methylation patterns display both tissue-specific and inter-individual differences suggestive of underlying function
Epigenetics ( IF 2.9 ) Pub Date : 2021-08-30 , DOI: 10.1080/15592294.2021.1950990
Philip Titcombe 1 , Robert Murray 2 , Matthew Hewitt 2 , Elie Antoun 2, 3 , Cyrus Cooper 1 , Hazel M Inskip 1, 4 , Joanna D Holbrook 2 , Keith M Godfrey 1, 2, 4 , Karen Lillycrop 2, 3 , Mark Hanson 2, 4 , Sheila J Barton 1
Affiliation  

ABSTRACT

DNA methylation (DNAm) in mammals is mostly examined within the context of CpG dinucleotides. Non-CpG DNAm is also widespread across the human genome, but the functional relevance, tissue-specific disposition, and inter-individual variability has not been widely studied. Our aim was to examine non-CpG DNAm in the wider methylome across multiple tissues from the same individuals to better understand non-CpG DNAm distribution within different tissues and individuals and in relation to known genomic regulatory features.

DNA methylation in umbilical cord and cord blood at birth, and peripheral venous blood at age 12–13 y from 20 individuals from the Southampton Women’s Survey cohort was assessed by Agilent SureSelect methyl-seq. Hierarchical cluster analysis (HCA) was performed on CpG and non-CpG sites and stratified by specific cytosine environment. Analysis of tissue and inter-individual variation was then conducted in a second dataset of 12 samples: eight muscle tissues, and four aliquots of cord blood pooled from two individuals.

HCA using methylated non-CpG sites showed different clustering patterns specific to the three base-pair triplicate (CNN) sequence. Analysis of CAC sites with non-zero methylation showed that samples clustered first by tissue type, then by individual (as observed for CpG methylation), while analysis using non-zero methylation at CAT sites showed samples grouped predominantly by individual. These clustering patterns were validated in an independent dataset using cord blood and muscle tissue.

This research suggests that CAC methylation can have tissue-specific patterns, and that individual effects, either genetic or unmeasured environmental factors, can influence CAT methylation.



中文翻译:


人类非 CpG 甲基化模式显示组织特异性和个体间差异,提示潜在功能


 抽象的


哺乳动物中的 DNA 甲基化 (DNAm) 主要在 CpG 二核苷酸的背景下进行检查。非 CpG DNAm 在人类基因组中也广泛存在,但其功能相关性、组织特异性分布和个体间变异尚未得到广泛研究。我们的目的是检查同一个体多个组织中更广泛的甲基化组中的非 CpG DNAm,以更好地了解不同组织和个体内的非 CpG DNAm 分布以及与已知基因组调控特征的关系。


采用 Agilent SureSelect 甲基测序技术对南安普顿妇女调查队列中 20 名个体的出生时脐带和脐带血以及 12-13 岁时外周静脉血中的 DNA 甲基化进行了评估。对 CpG 和非 CpG 位点进行层次聚类分析 (HCA),并按特定胞嘧啶环境进行分层。然后在包含 12 个样本的第二个数据集中进行组织和个体间变异分析:八个肌肉组织和来自两个个体的四份脐带血。


使用甲基化非 CpG 位点的 HCA 显示出特定于三碱基对三重 (CNN) 序列的不同聚类模式。对具有非零甲基化的 CAC 位点的分析表明,样品首先按组织类型进行聚类,然后按个体进行聚类(如 CpG 甲基化所观察到的),而使用 CAT 位点的非零甲基化进行分析表明,样品主要按个体进行分组。这些聚类模式在使用脐带血和肌肉组织的独立数据集中进行了验证。


这项研究表明,CAC 甲基化可以具有组织特异性模式,并且个体效应(无论是遗传因素还是未测量的环境因素)都可以影响 CAT 甲基化。

更新日期:2021-08-30
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