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

Sharma, Amitabh ; Halu, Arda ; Decano, Julius L. ; Padi, Megha ; Liu, Yang-yu ; Prasad, Rashmi B. LU ; Fadista, Joao LU ; Santolini, Marc ; Menche, Jörg and Weiss, Scott T. , et al. (2018) In npj Systems Biology and Applications 4(1).
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
npj Systems Biology and Applications
volume
4
issue
1
article number
25
publisher
Nature Publishing Group
external identifiers
  • scopus:85052687798
  • pmid:29977601
ISSN
2056-7189
DOI
10.1038/s41540-018-0057-0
language
English
LU publication?
yes
id
310ec991-6797-4b56-8de0-276d1f3399e2
date added to LUP
2018-07-05 15:59:23
date last changed
2024-02-13 22:52:24
@article{310ec991-6797-4b56-8de0-276d1f3399e2,
  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.}},
  author       = {{Sharma, Amitabh and Halu, Arda and Decano, Julius L. and Padi, Megha and Liu, Yang-yu and Prasad, Rashmi B. and Fadista, Joao and Santolini, Marc and Menche, Jörg and Weiss, Scott T. and Vidal, Marc and Silverman, Edwin K. and Aikawa, Masanori and Barabási, Albert-lászló and Groop, Leif and Loscalzo, Joseph}},
  issn         = {{2056-7189}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{npj Systems Biology and Applications}},
  title        = {{Controllability in an islet specific regulatory network identifies the transcriptional factor NFATC4, which regulates Type 2 Diabetes associated genes}},
  url          = {{http://dx.doi.org/10.1038/s41540-018-0057-0}},
  doi          = {{10.1038/s41540-018-0057-0}},
  volume       = {{4}},
  year         = {{2018}},
}