Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Oct 25;12(1):17856.
doi: 10.1038/s41598-022-22507-3.

Co-alterations of circadian clock gene transcripts in human placenta in preeclampsia

Guoli Zhou  1 , Emily Winn  2 , Duong Nguyen  3 , Eric P Kasten  4   5 , Margaret G Petroff  2   6 , Hanne M Hoffmann  7
Affiliations

Co-alterations of circadian clock gene transcripts in human placenta in preeclampsia

Guoli Zhou et al. Sci Rep. .

Abstract

Pre-eclampsia (PE) is a hypertensive condition that occurs during pregnancy and complicates up to 4% of pregnancies. PE exhibits several circadian-related characteristics, and the placenta possesses a functioning molecular clock. We examined the associations of 17 core circadian gene transcripts in placenta with PE vs. non-PE (a mixture of pregnant women with term, preterm, small-for-gestational-age, or chorioamnionitis) using two independent gene expression datasets: GSE75010-157 (80 PE vs. 77 non-PE) and GSE75010-173 (77 PE and 96 non-PE). We found a robust difference in circadian gene expression between PE and non-PE across the two datasets, where CRY1 mRNA increases and NR1D2 and PER3 transcripts decrease in PE placenta. Gene set variation analysis revealed an interplay between co-alterations of circadian clock genes and PE with altered hypoxia, cell migration/invasion, autophagy, and membrane trafficking pathways. Using human placental trophoblast HTR-8 cells, we show that CRY1/2 and NR1D1/2 regulate trophoblast migration. A subgroup study including only term samples demonstrated that CLOCK, NR1D2, and PER3 transcripts were simultaneously decreased in PE placenta, a finding supported by CLOCK protein downregulation in an independent cohort of human term PE placenta samples. These findings provide novel insights into the roles of the molecular clock in the pathogenesis of PE.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Bioinformatics pipeline to analyze circadian genes-correlated, PE-associated pathways.
Figure 2
Figure 2
HTR-8 cell migration is regulated by ligands targeting CRY1/2 and NR1D1/2. Wound healing assays in HTR-8 cells, show that (A, B) KL001, a drug stabilizing CRY1/2, but not KL101, a drug stabilizing CRY1, reduced HTR-8 cell migration. (C, D) PF670462, a drug preventing PER1/2/3 degradation, did not impact HTR-8 cell migration. (E–G) The NR1D1/2 agonist SR9009, had no significant effect on migration, whereas the NR1D1/2 antagonist/inverse agonist, SR8278, decreased HTR-8 cell migration. All drugs were tested at 1 and 10 µM. The data were pooled if the two doses were not significantly different. (B, D, F, G) Illustrative wound healing assay images. Dotted line on histograms represents approximate wound area in control at 24 h. Data is expressed as % change in average wound size from 0 h ± SEM. N = 3–6, in duplicate. One-way ANOVA repeated measures, *, p < 0.05; ***, p < 0.001.
Figure 3
Figure 3
CLOCK protein is reduced in term PE placenta. (A) Example westernblot image for CLOCK and beta-ACTIN (ACTIN), of indicated human placenta samples. (B) Histogram of CLOCK/ACTIN in human placenta. Each dot represents a sample. Two-way ANOVA, **, p < 0.001. n = 3–6/group. Sample labeled in orange was an outlier and excluded from statistical analysis.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Bibbins-Domingo K, et al. Screening for preeclampsia. JAMA. 2017;317:1661. - PubMed
    1. Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980–2010: Age-period-cohort analysis. BMJ. 2013;347:f6564. - PMC - PubMed
    1. Pauli JM, Repke JT. Preeclampsia. Obstet. Gynecol. Clin. N. Am. 2015;42:299–313. - PubMed
    1. Henderson JT, Thompson JH, Burda BU, Cantor A. Preeclampsia screening. JAMA. 2017;317:1668. - PubMed
    1. Heidrich M-B, Wenzel D, von Kaisenberg CS, Schippert C, von Versen-Höynck FM. Preeclampsia and long-term risk of cardiovascular disease: What do obstetrician-gynecologists know? BMC Pregnancy Childbirth. 2013;13:61. - PMC - PubMed

Publication types