Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.
Department of Public Health and Primary Care, Leuven University, Leuven, Belgium.
Aging (Albany NY). 2021 Jun 4;13(11):14630-14650. doi: 10.18632/aging.203117.
Telomere length (TL) and telomere shortening are biological indicators of aging, and epigenetic associates have been found for TL in adults. However, the role of epigenetic signatures in setting newborn TL and early life telomere dynamics is unknown. In the present study, based on 247 participating newborns from the ENVIRAGE birth cohort, whole-genome DNA methylation, profiled on the Illumina MethylationEPIC BeadChip microarray, and TL were measured in cord blood. In a follow-up visit at a mean age of 4.58 years, leukocyte TL was evaluated. We combined an epigenome-wide association study and a statistical learning method with re-sampling to select CpGs and their two-way interactions to model baseline (cord blood) TL and early-life telomere attrition rate, where distinct epigenetic signatures were identified for the two outcomes. In addition, a stronger epigenetic regulation was suggested in setting newborn TL than that of telomere dynamics in early life: 47 CpGs and 7 between-CpG interactions explained 76% of the variance in baseline TLs, while 72% of the total variance in telomere attrition rate was explained by 31 CpGs and 5 interactions. Functional enrichment analysis based on the selected CpGs in the two models revealed GLUT4 translocation and immune cell signaling pathways, respectively. These CpGs and interactions, as well as the cellular pathways, are potential novel targets of further investigation of telomere biology and aging.
端粒长度 (TL) 和端粒缩短是衰老的生物学指标，成年人的 TL 与表观遗传相关。然而，表观遗传特征在设定新生儿 TL 和早期生命端粒动态中的作用尚不清楚。在本研究中，基于 ENVIRAGE 出生队列的 247 名新生儿参与者，对脐带血中的全基因组 DNA 甲基化进行了分析，使用 Illumina MethylationEPIC BeadChip 微阵列进行了 profiling。在平均年龄为 4.58 岁的随访中，评估了白细胞 TL。我们结合全基因组关联研究和统计学习方法与重采样，选择 CpG 及其双向相互作用来建立模型，以模拟基线（脐带血）TL 和早期生命端粒损耗率，从而确定了两种结果的独特表观遗传特征。此外，在设定新生儿 TL 方面，表观遗传调控要强于早期生命中的端粒动态：47 个 CpG 和 7 个 CpG 间相互作用解释了基线 TL 变异的 76%，而 31 个 CpG 和 5 个相互作用解释了总端粒损耗率的 72%。基于两个模型中选定的 CpG 进行的功能富集分析显示了 GLUT4 易位和免疫细胞信号通路。这些 CpG 和相互作用以及细胞通路可能是进一步研究端粒生物学和衰老的潜在新目标。
