ABSTRACT

DNA methylation is highly sensitive to in utero perturbations and has an established role in both embryonic development and regulation of gene expression. The foetal genetic component has been previously shown to contribute significantly to the timing of birth, yet little is known about the identity and behaviour of individual genes. The aim of this study was to test the extent genome-wide DNA methylation levels in umbilical cord blood were associated with gestational age at birth (GA). Findings were validated in an independent sample and evidence for the regulation of gene expression was evaluated for cis gene relationships in specimens with multi-omic data. Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 450 K BeadChip, was associated with GA for 2,372 CpG probes (5% FDR) in both the Pregnancy, Race, Environment, Genes (PREG) and Newborn Epigenetic Study (NEST) cohorts. Significant probes mapped to 1,640 characterized genes and an association with nearby gene expression measures obtained by the Affymetrix HG-133A microarray was found for 11 genes. Differentially methylated positions were enriched for actively transcribed and enhancer chromatin states, were predominately located outside of CpG islands, and mapped to genes enriched for inflammation and innate immunity ontologies. In both PREG and NEST, the first principal component derived from these probes explained approximately one-half (58.1% and 47.8%, respectively) of the variation in GA. Gene pathways identified are consistent with the hypothesis of pathogen detection and response by the immune system to elicit premature labour as a consequence of unscheduled inflammation.

摘要

DNA甲基化对子宫内扰动高度敏感，并且在胚胎发育和基因表达调节中均具有确定的作用。先前已证明胎儿遗传成分对出生时机有重大贡献，但对单个基因的身份和行为知之甚少。这项研究的目的是测试脐带血中全基因组DNA甲基化水平与出生胎龄（GA）相关的程度。在独立的样本中对发现进行了验证，并评估了顺式对基因表达调控的证据具有多组学数据的样本中的基因关系。由Illumina Infinium人类甲基化450 K BeadChip测量的全基因组DNA甲基化与妊娠，种族，环境，基因（PREG）和新生儿表观遗传研究（NEST）中的2,372 CpG探针（5％FDR）的遗传算法相关队列。针对11个基因，发现了映射到1,640个特征基因的重要探针，以及与Affymetrix HG-133A微阵列获得的附近基因表达指标的关联。差异甲基化位置被富集以用于主动转录和增强染色质状态，主要位于CpG岛之外，并定位到针对炎症和先天免疫本体论而富集的基因。在PREG和NEST中，源自这些探针的第一主要成分解释了大约一半（58.1％和47.8％，GA的变化）。所鉴定的基因途径与病原体检测和免疫系统反应的假设相一致，该反应是由于计划外炎症引起的早产。