Early- and late-onset preeclampsia and the DNA methylation of circadian clock and clock-controlled genes in placental and newborn tissues

Abstract

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 clockcontrolled 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. ≤ 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.

Identifying key genes and drug screening for preeclampsia based on gene expression profiles

“…The circadian rhythm of blood pressure has been explored in relation to the severity and progression of PE ( 38 ). Van den Berg et al ( 39 ) also indicated that the DNA methylation status of circadian clock and clock-controlled genes in placental tissue was different between patients with PE and healthy controls.…”

Epigenetic Regulation of Circadian Rhythm and Its Possible Role in Diabetes Mellitus

“…Notably, epigenetic modifications can be inherited [137]. Factors like particulate air pollution [77], preeclampsia [138] or maternal circadian disruption [139] influence DNA methylation pattern in new-born and may have an impact on its health condition. Nonetheless, advances in the field of circadian disruption treatment are promising.…”

Role of Melatonin in Preterm Birth

“…Melatonin decreases in conditions associated with serious outcomes for the fetus and seems to be involved in preeclampsia and intrauterine growth restriction [11]. Melatonin treatment during human normal or abnormal pregnancy has been studied for a large range of conditions and at different times during the gestational period.…”

“…Bronchopulmonary dysplasia (BPD), a chronic lung disease that requires respiratory support at birth, is most frequently appeared in preterm infants whose gestation age <29 weeks [11]. Pathogenesis of BPD has been attributed to multiple factors, including prematurity of lung tissue, superabundant of the inflammatory state, and disruption of the repairing process following injury [12][13][14].…”

“…A successful pregnancy requires coordination from all the physiological parameters between mother and fetus. Alteration of these crucial features may result in preterm births [11][12][13][14][15][16]. Evidence suggests that maternal melatonin level is essential for fetal development and differential level of serum melatonin in pregnant and non-pregnant women has been reported ( Figure 1) [17,18].…”