School of Nursing and Health Studies, University of Miami, Coral Gables, FL, USA.
Gillings School of Global Public Health, Institute for Environmental Health Solutions, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
BMC Biol. 2023 Aug 23;21(1):173. doi: 10.1186/s12915-023-01662-7.
Health outcomes among children born prematurely are known to be sexually dimorphic, with male infants often more affected, yet the mechanism behind this observation is not clear. CpG methylation levels in the placenta and blood also differ by sex and are associated with adverse health outcomes. We contrasted CpG methylation levels in the placenta and neonatal blood (n = 358) from the Extremely Low Gestational Age Newborn (ELGAN) cohort based on the EPIC array, which assays over 850,000 CpG sites across the epigenome. Sex-specific epigenome-wide association analyses were conducted for the placenta and neonatal blood samples independently, and the results were compared to determine tissue-specific differences between the methylation patterns in males and females. All models were adjusted for cell type heterogeneity. Enrichment pathway analysis was performed to identify the biological functions of genes related to the sexually dimorphic CpG sites.
Approximately 11,500 CpG sites were differentially methylated in relation to sex. Of these, 5949 were placenta-specific and 5361 were blood-specific, with only 233 CpG sites overlapping in both tissues. For placenta-specific CpG sites, 90% were hypermethylated in males. For blood-specific CpG sites, 95% were hypermethylated in females. In the placenta, keratinocyte differentiation biological pathways were enriched among the differentially methylated genes. No enrichment pathways were observed for blood.
Distinct methylation patterns were observed between male and female children born extremely premature, and keratinocyte differentiation pathways were enriched in the placenta. These findings provide new insights into the epigenetic mechanisms underlying sexually dimorphic health outcomes among extremely premature infants.
早产儿的健康结果存在性别二态性，男婴通常受影响更严重，但这种观察结果的背后机制尚不清楚。胎盘和血液中的 CpG 甲基化水平也因性别而异，与不良健康结果相关。我们根据 EPIC 阵列对比了来自极度低胎龄新生儿（ELGAN）队列的胎盘和新生儿血液（n=358）中的 CpG 甲基化水平，该阵列检测了整个表观基因组中超过 850,000 个 CpG 位点。分别对胎盘和新生儿血液样本进行了基于性别的全基因组表观遗传关联分析，并对结果进行了比较，以确定男性和女性之间甲基化模式的组织特异性差异。所有模型均针对细胞类型异质性进行了调整。进行了富集途径分析，以确定与性二态性 CpG 位点相关的基因的生物学功能。
大约有 11500 个 CpG 位点与性别相关存在差异甲基化。其中，5949 个是胎盘特异性的，5361 个是血液特异性的，只有 233 个 CpG 位点在两种组织中重叠。对于胎盘特异性 CpG 位点，90%在男性中呈高甲基化。对于血液特异性 CpG 位点，95%在女性中呈高甲基化。在胎盘组织中，角质形成细胞分化的生物学途径在差异甲基化基因中富集。在血液中没有观察到富集途径。
在极早产儿中，男性和女性之间观察到了不同的甲基化模式，角质形成细胞分化途径在胎盘组织中富集。这些发现为极度早产儿健康结果存在性别二态性的表观遗传机制提供了新的见解。
