Construction of Glycometabolism- and Hormone-Related lncRNA-Mediated Feedforward Loop Networks Reveals Global Patterns of lncRNAs and Drug Repurposing in Gestational Diabetes.

Xuelian Fu,Shuyu Zhao,Tianyi Liu,Yan Li,Nan Lv,Huifang Cong,Yuhong Sun

doi:10.3389/fendo.2020.00093

Abstract

Gestational diabetes mellitus (GDM) is a condition associated with the onset of abnormal glucose tolerance during pregnancy. Long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and genes can form lncRNA-mediated feedforward loops (lnc-FFLs), which are functional network motifs that regulate a wide range of biological processes and diseases. However, lnc-FFL network motifs have not been systematically investigated in GDM, and their role in the disease remains largely unknown. In the present study, a global lnc-FFL network was constructed and analyzed. Glycometabolism- and hormone-related lnc-FFL networks were extracted from the global network. An integrated algorithm was designed to identify dysregulated glycometabolism- and hormone-related lnc-FFLs in GDM. The patterns of dysregulated lnc-FFLs in GDM were complex. Moreover, there were strong associations between dysregulated glycometabolism- and hormone-related lnc-FFLs in GDM. Core modules were extracted from the dysregulated lnc-FFL networks in GDM and showed specific and essential functions. In addition, dysregulated lnc-FFLs could combine with ceRNAs and form more complex modules, which could play novel roles in GDM. Notably, we discovered that the dysregulated lnc-FFLs were enriched in the thyroid hormone signaling pathway. Some drug-repurposing candidates, such as hormonal drugs, could be identified based on lnc-FFLs in GDM. In summary, the present study highlighted the effect of dysregulated glycometabolism- and hormone-related lnc-FFLs in GDM and revealed their potential for the discovery of novel biomarkers and therapeutic targets for GDM.

Highlights

Gestational diabetes mellitus (GDM), or glucose intolerance with first onset and recognition in pregnancy, is a common disease among pregnant women [1]
Construction and Analysis of Glycometabolism- and Hormone-Related lnc-FFL Networks lnc-FFL is defined as a regulatory motif whereby a gene regulates an Long non-coding RNAs (lncRNAs) and an miRNA while the miRNA regulates the lncRNA
Previous study suggested that glycometabolism and hormones are two highly influential factors in GDM [8, 10]

Summary

Introduction

Gestational diabetes mellitus (GDM), or glucose intolerance with first onset and recognition in pregnancy, is a common disease among pregnant women [1]. Marked changes occur during maternal metabolism, and many of these are essential for healthy fetal growth and development They may lead to GDM and other diseases if there is a substantial deviation from the physiological gestational levels [6, 7]. Fetal exposure to hyperglycemia during a critical developmental period may have long-term effects on the fetus by creating a metabolic memory, known as fetal programming [9] Certain hormones, such as progestogens, estrogens, and androgens, are essential for the successful establishment and maintenance of pregnancy and the proper development of the fetus. There are strong associations between glycometabolism, hormones, and GDM, the details of the mechanism are unknown

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Results

Conclusion