Journal
FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.883971
Keywords
intrahepatic cholestasis of pregnancy; ceRNA; immunity-related molecules; birth weight; placenta weight; bioinformatics analysis
Categories
Funding
- Chongqing Science and Health Joint Medical Research Project [2019ZDXM030]
- Science and Technology Research Project of Chongqing Municipal Education Commission [KJQN201900434]
- Natural Science Foundation of Chongqing, China [cstc2021jcyj-bsh0055]
- Program for Youth Innovation in Future Medicine, Chongqing Medical University in 2021 [W0058]
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This study is the first to evaluate the ceRNA networks in placenta of patients with pregnancy-related intrahepatic cholestasis (ICP), and it shows that alterations in immune regulatory networks may impact fetal and placental growth. The findings suggest that ceRNA regulatory network may improve biomarker predictions for developing novel therapeutic approaches in ICP.
Pregnancy-related intrahepatic cholestasis (ICP) is a serious complication with adverse perinatal outcomes of preterm labor, fetal distress, or stillbirth. As a result, it is important to investigate and identify the potential critical pathogenic mechanisms of ICP. First, we collected the placental tissues from the ICP with placental weight and fetal birth weight loss for the whole transcriptome sequencing. Then we analyzed the differentially expressed (DE) circRNAs (DEcircRNAs) by SRPBM, DElncRNAs by FRKM, DEmiRNAs by TPM, and DEmRNAs by TPM and RSEM. Based on differential expression of term pregnancy placental tissues from pregnancies impacted by ICP (n=7) as compared to gestational aged matched control tissues (n=5), the circ/lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) regulatory networks were constructed. The ceRNA regulatory networks covered 3,714 events, including 21 DEmiRNAs, 36 DEcircRNAs, 146 DElncRNAs, and 169 DEmRNAs. According to the functional analysis, ICP complications were linked to the immune system, signal transduction, endocrine system, cell growth and death, and transport and catabolism. Further evidence suggested that the expression of immune-related genes KLRD1, BRAF, and NFATC4 might have a potential ceRNA mechanism by individual lncRNA sponging miR372-3p, miR-371a-3p, miR-7851-3p, and miR-449a to control downstream the level of TNF-alpha, IFN-gamma, and IL-10, thereby regulating the pathophysiology of ICP. Furthermore, our results were validated by the qRT-PCR, western blotting and ELISA assays. In conclusion, this study is the first to evaluate placental ceRNA networks in pregnancies affected by ICP, showing alterations in immune regulatory networks which may impact fetal and placental growth. Overall our these data suggest that the ceRNA regulatory network may refine biomarker predictions for developing novel therapeutic approaches in ICP.
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