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

Overview of the approach to identify the key pathways in T2D using control centrality approach. a Gene expression data: Pancreatic islets from cadaver donors (54 nondiabetic and 9 diabetic) were used to construct the gene regulatory network (GRN) and extended by adding kinase and signaling links. The largest connected component of the extended GRN (EGRN) consists of N？=？3084 genes and M？=？7935 edges. b The control centrality measure is used to quantify the relative importance of each gene in EGRN relative to T2D. c High control centrality (HiCc) pathways are found by comparing the control centrality distribution of genes within the pathway vs the control centrality distribution of all other genes in EGRN. Pathways with a significantly higher control centrality distribution compared to the background are deemed HiCc pathways. For example, the Gap junction pathway emerges as a HiCc pathway, whereas the Huntington’s Disease pathway is found to be a non-HiCc pathway. d In vitro silencing experiments are performed on genes implicated in a large number of HiCc pathways, such as NFATC4, to discover novel mechanistic connections with known T2D gene