Controllability in an islet specific regulatory network identifies the transcriptional factor NFATC4, which regulates Type 2 Diabetes associated genes

Amitabh Sharma, Arda Halu, Julius L. Decano, Megha Padi, Yang Yu Liu, Rashmi B. Prasad, Joao Fadista, Marc Santolini, Jörg Menche, Scott T. Weiss, Marc Vidal, Edwin K. Silverman, Masanori Aikawa, Albert László Barabási, Leif Groop, Joseph Loscalzo

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Probing the dynamic control features of biological networks represents a new frontier in capturing the dysregulated pathways in complex diseases. Here, using patient samples obtained from a pancreatic islet transplantation program, we constructed a tissue-specific gene regulatory network and used the control centrality (Cc) concept to identify the high control centrality (HiCc) pathways, which might serve as key pathobiological pathways for Type 2 Diabetes (T2D). We found that HiCc pathway genes were significantly enriched with modest GWAS p-values in the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) study. We identified variants regulating gene expression (expression quantitative loci, eQTL) of HiCc pathway genes in islet samples. These eQTL genes showed higher levels of differential expression compared to non-eQTL genes in low, medium, and high glucose concentrations in rat islets. Among genes with highly significant eQTL evidence, NFATC4 belonged to four HiCc pathways. We asked if the expressions of T2D-associated candidate genes from GWAS and literature are regulated by Nfatc4 in rat islets. Extensive in vitro silencing of Nfatc4 in rat islet cells displayed reduced expression of 16, and increased expression of four putative downstream T2D genes. Overall, our approach uncovers the mechanistic connection of NFATC4 with downstream targets including a previously unknown one, TCF7L2, and establishes the HiCc pathways’ relationship to T2D.

Original languageEnglish (US)
Article number25
Journalnpj Systems Biology and Applications
Volume4
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Modeling and Simulation
  • Biochemistry, Genetics and Molecular Biology(all)
  • Drug Discovery
  • Computer Science Applications
  • Applied Mathematics

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