Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Centre for Molecular Medicine and Therapeutics, BC Children's Hospital, Vancouver, BC, Canada.
Epigenetics Chromatin. 2019 Jan 2;12(1):1. doi: 10.1186/s13072-018-0245-6.
The widespread use of accessible peripheral tissues for epigenetic analyses has prompted increasing interest in the study of tissue-specific DNA methylation (DNAm) variation in human populations. To date, characterizations of inter-individual DNAm variability and DNAm concordance across tissues have been largely performed in adult tissues and therefore are limited in their relevance to DNAm profiles from pediatric samples. Given that DNAm patterns in early life undergo rapid changes and have been linked to a wide range of health outcomes and environmental exposures, direct investigations of tissue-specific DNAm variation in pediatric samples may help inform the design and interpretation of DNAm analyses from early life cohorts. In this study, we present a systematic comparison of genome-wide DNAm patterns between matched pediatric buccal epithelial cells (BECs) and peripheral blood mononuclear cells (PBMCs), two of the most widely used peripheral tissues in human epigenetic studies. Specifically, we assessed DNAm variability, cross-tissue DNAm concordance and genetic determinants of DNAm across two independent early life cohorts encompassing different ages.
BECs had greater inter-individual DNAm variability compared to PBMCs and highly the variable CpGs are more likely to be positively correlated between the matched tissues compared to less variable CpGs. These sites were enriched for CpGs under genetic influence, suggesting that a substantial proportion of DNAm covariation between tissues can be attributed to genetic variation. Finally, we demonstrated the relevance of our findings to human epigenetic studies by categorizing CpGs from published DNAm association studies of pediatric BECs and peripheral blood.
Taken together, our results highlight a number of important considerations and practical implications in the design and interpretation of EWAS analyses performed in pediatric peripheral tissues.
可及的周围组织在进行表观遗传学分析方面的广泛应用，促使人们对人类群体中组织特异性 DNA 甲基化（DNAm）变异的研究产生了浓厚的兴趣。迄今为止，个体间 DNAm 变异性和组织间 DNAm 一致性的特征主要在成人组织中进行，因此它们与儿科样本中的 DNAm 谱相关性有限。鉴于生命早期的 DNAm 模式发生快速变化，并且与广泛的健康结果和环境暴露有关，直接研究儿科样本中的组织特异性 DNAm 变异可能有助于为生命早期队列的 DNAm 分析的设计和解释提供信息。在这项研究中，我们对匹配的儿科颊上皮细胞（BEC）和外周血单核细胞（PBMC）之间的全基因组 DNAm 模式进行了系统比较，这两种组织是人类表观遗传学研究中最广泛使用的两种周围组织。具体来说，我们评估了两个不同年龄的独立早期生命队列中 DNAm 变异性、跨组织 DNAm 一致性和 DNAm 的遗传决定因素。
BEC 与 PBMC 相比，个体间 DNAm 变异性更大，并且高度可变的 CpG 比低可变的 CpG 更有可能在匹配的组织之间呈正相关。这些位点富含受遗传影响的 CpG，表明组织间 DNAm 变异的很大一部分可以归因于遗传变异。最后，我们通过对已发表的儿科 BEC 和外周血的 DNAm 关联研究的 CpG 进行分类，证明了我们的研究结果对人类表观遗传学研究的相关性。
总之，我们的研究结果强调了在儿科周围组织中进行 EWAS 分析的设计和解释中需要考虑的一些重要因素和实际意义。
