Title:Interplay of miRNA-TF-Gene Through a Novel Six-node Feed-forward
Loop Identified Inflammatory Genes as Key Regulators in Type-2 Diabetes
Volume: 19
Issue: 1
Author(s): Gayathri Shama Bhat, Tarakad Ranganatha Keshav, Raghu Chandrashekar Hariharapura and Shaik Mahammad Abdul Fayaz*
Affiliation:
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal,
576104, Karnataka, India
- Manipal Center for Infectious Diseases,
Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
Keywords:
Systems biology, gene regulatory network, type 2 diabetes, feed-forward loop, network motifs, inflammation.
Abstract:
Background: Intricacy in the pathological processes of type 2 diabetes (T2D) invites a need
to understand gene regulation at the systems level. However, deciphering the complex gene modulation
requires regulatory network construction.
Objective: The study aims to construct a six-node feed-forward loop (FFL) to analyze all the diverse
inter- and intra- interactions between microRNAs (miRNA) and transcription factors (TF) involved in
gene regulation.
Methods: The study included 644 genes, 64 TF, and 448 miRNA. A cumulative hypergeometric test
was employed to identify the significant miRNA-miRNA and miRNA-TF interaction pairs. In addition,
experimentally proven TF-TF pairs were incorporated for the first time in the regulatory network to
discern gene regulation. The networks were analyzed to identify crucial genes involved in T2D.
Following this, gene ontology was predicted to recognize the biological function that is crucial in T2D.
Results: In T2D, the lowest gene regulation for a composite FFL occurs through a four-node FFL
variant1 (TF- miRNA-miRNA-Gene, n=14) and the highest regulation via a five-node FFL variant2
(TF-TF-miRNA-Gene, n=353). However, the maximum gene regulation occurs via six-node miRNA
FFL (miRNA-miRNA-TF-TF-gene-gene, n=23987). Subnetworks derived from the six-node miRNATF-
gene regulatory networks identified interactions among TP53 and NFkB, hsa-miR-125-5p and hsamiR-
155-5p.
Conclusion: The core regulation occurs through TP53, NFkB, hsa-miR-125-5p, and hsa-miR-155-5p
FFL implicating the association of inflammation in the pathogenesis of T2D, which occurs majorly via
six-node miRNA FFL. Thus regulatory network provides broader insights into the pathogenesis of T2D
and can be extended to study the inflammatory mechanisms in various infections.
