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NPJ Syst Biol Appl. 2018 Jul 3;4:25. doi: 10.1038/s41540-018-0057-0. eCollection 2018.

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

Author information

1
1Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.
2
2Center for Complex Network Research and Department of Physics, Northeastern University, Boston, MA 02115 USA.
3
3Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215 USA.
4
4Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215 USA.
5
5Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721 USA.
6
6Lund University Diabetes Center, Department of Clinical Sciences, Diabetes & Endocrinology, Skåne University Hospital Malmö, Lund University, Malmö, 20502 Sweden.
7
7 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090 Austria.
8
8Department of Genetics, Harvard Medical School, Boston, MA 02115 USA.
9
9Center for Network Science, Central European University, Nador u. 9, 1051 Budapest, Hungary.
10
10Department of Clinical Sciences, Islet cell physiology, Skåne University Hospital Malmö, Lund University, Malmö, 20502 Sweden.
11
11Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.
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Contributed equally

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.

Conflict of interest statement

In the past three years, E.K.S. received honoraria and consulting fees from Merck, grant support and consulting fees from GlaxoSmithKline, and honoraria and travel support from Novartis. J.L. discloses a relevant conflict for his founder’s role with Scipher, Inc. (a network medicine company).

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