van den Berg C B, Chaves I, Herzog E M, Willemsen S P, van der Horst G T J, Steegers-Theunissen R P M
a Department of Obstetrics and Gynecology , Division of Obstetrics & Prenatal Medicine, Erasmus University Medical Center , Rotterdam , The Netherlands.
b Department of Molecular Genetics , Erasmus University Medical Center , Rotterdam , The Netherlands.
Chronobiol Int. 2017;34(7):921-932. doi: 10.1080/07420528.2017.1326125. Epub 2017 Jun 14.
The placenta is important in providing a healthy environment for the fetus and plays a central role in the pathophysiology of preeclampsia (PE). Fetal and placental developments are influenced by epigenetic programming. There is some evidence that PE is controlled to an altered circadian homeostasis. In a nested case-control study embedded in the Rotterdam Periconceptional Cohort, we obtained placental tissue, umbilical cord leukocytes (UCL), and human umbilical venous endothelial cells of 13 early-onset PE, 16 late-onset PE and 83 controls comprising 36 uncomplicated and 47 complicated pregnancies, i.e. 27 fetal growth restricted and 20 spontaneous preterm birth. To investigate the associations between PE and the epigenetics of circadian clock and clock-controlled genes in placental and newborn tissues, genome-wide DNA methylation analysis was performed using the Illumina HumanMethylation450K BeadChip and a candidate-gene approach using ANCOVA was applied on 939 CpGs of 39 circadian clock and clock-controlled genes. DNA methylation significantly differed in early-onset PE compared with spontaneous preterm birth at 6 CpGs in placental tissue (3.73 ≤ p ≤ 0.016) and at 21 CpGs in UCL (1.09≤ p ≤ 0.024). In early-onset PE compared with fetal growth restriction 2 CpGs in placental tissue (p < 0.05) and 8 CpGs in uncomplicated controls (4.78≤ p ≤ 0.049) were significantly different. Moreover, significantly different DNA methylation in early-onset PE compared with uncomplicated controls was shown at 6 CpGs in placental tissue (1.36≤ p ≤ 0.045) and 11 CpGs in uncomplicated controls (2.52≤ p ≤ 0.009). No significant associations were shown with late-onset PE between study groups or tissues. The most differentially methylated CpGs showed hypomethylation in placental tissue and hypermethylation in uncomplicated controls. In conclusion, DNA methylation of circadian clock and clock-controlled genes demonstrated most differences in UCL of early-onset PE compared with spontaneous preterm birth. Implications of the tissue-specific variations in epigenetic programming for circadian performance and long-term health need further investigation.
胎盘对于为胎儿提供健康环境至关重要，并且在子痫前期（PE）的病理生理学中起着核心作用。胎儿和胎盘的发育受表观遗传编程的影响。有证据表明，PE受昼夜节律稳态改变的控制。在鹿特丹围孕期队列中的一项巢式病例对照研究中，我们获取了13例早发型PE、16例晚发型PE以及83例对照（包括36例无并发症妊娠和47例并发症妊娠，即27例胎儿生长受限和20例自发性早产）的胎盘组织、脐带白细胞（UCL）和人脐静脉内皮细胞。为了研究PE与胎盘和新生儿组织中生物钟及生物钟调控基因的表观遗传学之间的关联，使用Illumina HumanMethylation450K BeadChip进行了全基因组DNA甲基化分析，并对39个生物钟及生物钟调控基因的939个CpG位点采用ANCOVA的候选基因方法。与自发性早产相比，早发型PE胎盘组织中的6个CpG位点（3.73≤p≤0.016）和UCL中的21个CpG位点（1.09≤p≤0.024）的DNA甲基化存在显著差异。与胎儿生长受限相比，早发型PE胎盘组织中的2个CpG位点（p<0.05）以及无并发症对照中的8个CpG位点（4.78≤p≤0.049）存在显著差异。此外，与无并发症对照相比，早发型PE胎盘组织中的6个CpG位点（1.36≤p≤0.045）和无并发症对照中的11个CpG位点（2.52≤p≤0.009）的DNA甲基化存在显著差异。研究组或组织之间与晚发型PE未显示出显著关联。差异最大的甲基化CpG位点在胎盘组织中表现为低甲基化，在无并发症对照中表现为高甲基化。总之，与自发性早产相比，早发型PE的UCL中生物钟及生物钟调控基因的DNA甲基化差异最为明显。表观遗传编程中组织特异性变化对昼夜节律表现和长期健康的影响需要进一步研究。
