Upregulation of T Cell Receptor Signaling Pathway Components in Gestational Diabetes Mellitus Patients: Joint Analysis of mRNA and circRNA Expression Profiles.

Yan-Ming Chen,Qiong Zhu,Lin-Dan Ji,Jin Xu,Bin-Bin Yao,Zhi-Jia Zhao,Jie Cai,Li-Ming Zhou

doi:10.3389/fendo.2021.774608

Yan-Ming Chen, Qiong Zhu + Show 6 more

Open Access

https://doi.org/10.3389/fendo.2021.774608

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Abstract

ObjectiveGestational diabetes mellitus (GDM) is one of the most common complications of pregnancy, and its pathogenesis is still unclear. Studies have shown that circular RNAs (circRNAs) can regulate blood glucose levels by targeting mRNAs, but the role of circRNAs in GDM is still unknown. Therefore, a joint microarray analysis of circRNAs and their target mRNAs in GDM patients and healthy pregnant women was carried out.MethodsIn this study, microarray analyses of mRNA and circRNA in 6 GDM patients and 6 healthy controls were conducted to identify the differentially expressed mRNA and circRNA in GDM patients, and some of the discovered mRNAs and circRNAs were further validated in additional 56 samples by quantitative realtime PCR (qRT-PCR) and droplet digital PCR (ddPCR).ResultsGene ontology and pathway analyses showed that the differentially expressed genes were significantly enriched in T cell immune-related pathways. Cross matching of the differentially expressed mRNAs and circRNAs in the top 10 KEGG pathways identified 4 genes (CBLB, ITPR3, NFKBIA, and ICAM1) and 4 corresponding circRNAs (circ-CBLB, circ-ITPR3, circ-NFKBIA, and circ-ICAM1), and these candidates were subsequently verified in larger samples. These differentially expressed circRNAs and their linear transcript mRNAs were all related to the T cell receptor signaling pathway, and PCR results confirmed the initial microarray results. Moreover, circRNA/miRNA/mRNA interactions and circRNA-binding proteins were predicted, and circ-CBLB, circ-ITPR3, and circ-ICAM1 may serve as GDM-related miRNA sponges and regulate the expression of CBLB, ITPR3, NFKBIA, and ICAM1 in cellular immune pathways.ConclusionUpregulation of T cell receptor signaling pathway components may represent the major pathological mechanism underlying GDM, thus providing a potential approach for the prevention and treatment of GDM.

Highlights

Gestational diabetes mellitus (GDM) refers to varying degrees of impaired glucose tolerance that occur for the first time during pregnancy, and it is one of the most common complications of pregnancy [1]
Samples from 6 pairs were randomly selected for mRNA/circRNA microarray analysis, and samples from the remaining 28 pairs were tested for followup verification
There was no significant difference in the general characteristic indices between the two groups, except for the significantly higher oral glucose tolerance test (OGTT) level in the GDM group; these results indicated that the baseline indices of the two groups were well matched

Summary

Introduction

Gestational diabetes mellitus (GDM) refers to varying degrees of impaired glucose tolerance that occur for the first time during pregnancy, and it is one of the most common complications of pregnancy [1]. According to the latest global diabetes map released by the International Diabetes Federation, the worldwide prevalence of gestational hyperglycemia in 2019 was 15.8%, and GDM accounted for 83.6% of these cases [2]. The latest epidemiological surveys show that the prevalence rate of GDM in China ranges from 17.6 to 18.3% [3, 4], which is considerably higher than the global average. The abnormal increase in blood glucose levels in GDM patients markedly increases the incidence of adverse pregnancy outcomes. A large number of studies have shown that GDM increases the risk of maternal miscarriage, cesarean section, postpartum hemorrhage, preeclampsia, neonatal macrosomia, infants larger than gestational age, and congenital malformations, and GDM leads to an increased future risk of type 2 diabetes (T2D) and cardiovascular disease for mothers and offsprings [5]

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