Associations between infant sex and DNA methylation across umbilical cord blood, artery, and placenta samples

DNA methylation (DNAm) is vulnerable to dysregulation by environmental exposures during epigenetic reprogramming that occurs in embryogenesis. Sexual dimorphism in environmentally induced DNAm dysregulation has been identified and therefore it is important to understand sex-specific DNAm patterns. DNAm at several autosomal sites has been consistently associated with sex in cord blood and placental foetal tissues. However, there is limited research comparing sex-specific DNAm across tissues, particularly differentially methylated regions (DMRs). This study leverages DNAm data measured using the Illumina HumanMethylation450 BeadChip in cord blood (N = 179), placenta (N = 229), and umbilical artery samples (N = 229) in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort to identify autosomal DMRs and differentially methylated positions (DMPs). A replication analyses was conducted in an independent cohort (GEO Accession GSE129841). We identified 183, 257, and 419 DMRs and 2119, 2281, and 3405 DMPs (<i>p_Bonferroni</i> &lt; 0.05) in cord blood, placenta, and artery samples, respectively. Thirty-nine DMRs overlapped in all three tissues, overlapping with genes involved in spermatogenesis (<i>NKAPL, PIWIL2 and AURKC</i>) and X–inactivation (<i>LRIF1</i>). In replication analysis, 85% of DMRs overlapped with those identified in PRISM. Overall, DMRs and DMPs had higher methylation levels among females in cord blood and artery samples, but higher methylation levels among males in placenta samples. Further research is necessary to understand biological mechanisms that contribute to differences in sex-specific DNAm signatures across tissues, as well as to determine if sexual dimorphism in the epigenome impacts response to environmental stressors.

DNA甲基化（DNA methylation, DNAm）在胚胎发生过程中发生的表观遗传重编程阶段，易受环境暴露引发的调控异常。现有研究已证实环境诱导的DNAm调控异常存在性别二态性，因此解析性别特异性DNAm模式具有重要科学意义。此前多项研究一致发现，脐带血与胎盘胎儿组织中多个常染色体位点的DNAm水平与性别显著相关。然而，目前针对不同组织间性别特异性DNAm差异的比较研究仍较为匮乏，尤其是针对差异甲基化区域（differentially methylated regions, DMRs）的相关研究。本研究依托代际应激机制编程（PRogramming of Intergenerational Stress Mechanisms, PRISM）队列，采用Illumina HumanMethylation450微珠芯片检测了该队列中脐带血（样本量N=179）、胎盘（N=229）及脐动脉样本（N=229）的DNAm数据，以此筛选常染色体DMRs与差异甲基化位点（differentially methylated positions, DMPs）。随后本研究在独立队列（基因表达综合数据库Gene Expression Omnibus, GEO 登录号GSE129841）中开展了验证分析。本研究分别在脐带血、胎盘及脐动脉样本中鉴定出183、257、419个DMRs，以及2119、2281、3405个DMPs（邦费罗尼校正后的P值<0.05）。其中39个DMRs在三类组织中均存在重叠，这些区域涉及精子发生相关基因（NKAPL、PIWIL2及AURKC）与X染色体失活相关基因（LRIF1）。验证分析结果显示，85%的PRISM队列鉴定得到的DMRs在独立队列中得以重复。整体而言，脐带血与脐动脉样本中女性的DNAm水平更高，而胎盘样本中男性的DNAm水平更高。未来仍需开展进一步研究，以阐明不同组织间性别特异性DNAm特征差异的生物学机制，并明确表观基因组的性别二态性是否会影响机体对环境应激源的应答反应。