Controllability in an islet specific regulatory network identifies the transcriptional factor NFATC4, which regulates Type 2 Diabetes associated genes
Decano, Julius L
Prasad, Rashmi B
Weiss, Scott T
Silverman, Edwin K
AffiliationUniv Arizona, Dept Mol & Cellular Biol
MetadataShow full item record
PublisherNATURE PUBLISHING GROUP
CitationSharma, A., Halu, A., Decano, J. L., Padi, M., Liu, Y. Y., Prasad, R. B., ... & Vidal, M. (2018). Controllability in an islet specific regulatory network identifies the transcriptional factor NFATC4, which regulates Type 2 Diabetes associated genes. NPJ systems biology and applications, 4(1), 25.
Rights© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License.
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AbstractProbing 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.
NoteOpen access journal
VersionFinal published version
SponsorsNational Institutes of Health (NIH) [P01HL13285, R01HL118455, P50-HG004233-CEGS, U01HL108630, P01 HL083069, U01 HL065899, P01 HL105339, R01HL111759, RC HL10154301]