Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Mar 6;11:93.
doi: 10.3389/fendo.2020.00093. eCollection 2020.

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

Affiliations
Free PMC article

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

Xuelian Fu et al. Front Endocrinol (Lausanne). .
Free PMC article

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.

Keywords: drug repurposing; gestational diabetes; glycometabolism; hormone; lncRNA-mediated feedforward loop; thyroid hormone.

Figures

Figure 1
Figure 1
Construction and analysis of glycometabolism- and hormone-related lnc-FFL networks. (A) A global lnc-FFL network based on experimentally verified interaction data. lncRNAs, miRNAs, and genes are colored in green, yellow, and red, respectively. (B) Bar plot, showing the number of lncRNAs, miRNAs, and genes in the global lnc-FFLs network. (C) The degree distribution of the global lnc-FFL network. (D) Venn diagram, showing the intersection between glycometabolism- and hormone-related genes. (E) The glycometabolism-related lnc-FFL network. (F) The hormone-related lnc-FFL network.
Figure 2
Figure 2
The dysregulated glycometabolism- and hormone-related lnc-FFL networks. (A) The dysregulated glycometabolism-related lnc-FFL network. (B) The dysregulated hormone-related lnc-FFL network. (C–E) Density distribution curves of CSdif, CSPCC, and final score, respectively, in dysregulated glycometabolism- and hormone-related lnc-FFL networks. (F,G) Two examples showing dysregulated patterns of lnc-FFLs in GDM.
Figure 3
Figure 3
Common and specific features of dysregulated glycometabolism- and hormone-related lnc-FFLs. (A) Venn diagram showing the intersection between dysregulated glycometabolism- and hormone-related lnc-FFLs. (B) The glycometabolism-related lnc-FFL network in GDM. (C) The hormone-related dysregulated lnc-FFL network in GDM. (D) An example showing the common dysregulated lnc-FFLs in GDM. (E) lncRNA, miRNA, and gene expression levels in a common dysregulated lnc-FFL.
Figure 4
Figure 4
Core modules extracted from common dysregulated lnc-FFL networks, showing specific functions. (A) A key module that contains the node with the highest degree and its neighbors. (B) A core module extracted from dysregulated lnc-FFL networks associated with GDM. (C) Heat map showing the p-values of pathway enrichment analysis with red representing more significant p-values. (D) Bar plot showing the p-values of significantly enriched GO terms. (E) An example, showing that ceRNAs and dysregulated lnc-FFLs combine to form more complex modules.
Figure 5
Figure 5
Candidate drug repurposing based on dysregulated lnc-FFLs associated with GDM. (A) The thyroid hormone pathway, and enriched target genes of miRNAs in dysregulated lnc-FFLs associated with GDM. (B) Drug-related dysregulated lnc-FFL networks. The square represents drugs and the circle represents genes, lncRNAs, and miRNAs. (C) Pie chart showing the percent of anti-inflammatory and hormonal drugs. (D) Candidate drug repurposing of the ESPRA-related lnc-FFL.

Similar articles

See all similar articles

References

    1. Kramer CK, Campbell S, Retnakaran R. Gestational diabetes and the risk of cardiovascular disease in women: a systematic review and meta-analysis. Diabetologia. (2019) 62:905–14. 10.1007/s00125-019-4840-2 - DOI - PubMed
    1. Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet. (2009) 373:1773–9. 10.1016/S0140-6736(09)60731-5 - DOI - PubMed
    1. Beharier O, Shoham-Vardi I, Pariente G, Sergienko R, Kessous R, Baumfeld Y, et al. . Gestational diabetes mellitus is a significant risk factor for long-term maternal renal disease. J Clin Endocrinol Metab. (2015) 100:1412–6. 10.1210/jc.2014-4474 - DOI - PubMed
    1. Di Cianni G, Ghio A, Resi V, Volpe L. Gestational diabetes mellitus: an opportunity to prevent type 2 diabetes and cardiovascular disease in young women. Womens Health. (2010) 6:97–105. 10.2217/WHE.09.76 - DOI - PubMed
    1. Zhang C, Ning Y. Effect of dietary and lifestyle factors on the risk of gestational diabetes: review of epidemiologic evidence. Am J Clin Nutr. (2011) 94(6 Suppl):1975S−9S. 10.3945/ajcn.110.001032 - DOI - PMC - PubMed

Publication types

LinkOut - more resources

Feedback