In silico and functional analysis identifies key gene networks and novel gene candidates in obesity-linked human
Lijin Wang1, Pratap Veerabrahma Seshachalam2, Ruiming Chua3,4
1Centre for Computational Biology, Duke-NUS Medical School, Singapore.
Objective:
Visceral adiposity is associated with increased proinflammatory activity, insulin resistance, diabetes risk, and mortality rate. Numerous individual genes have been associated with obesity, but studies investigating gene regulatory networks in human visceral obesity have been lacking.
Methods:
We analyzed gene regulatory networks in human visceral adipose tissue (VAT) from 48 and 11 Chinese patients with and without obesity, respectively, using gene coexpression and gene regulatory network construction from RNA-sequencing data. We also conducted RNA interference-based functional tests on selected genes for effects on adipocyte differentiation.
Results:
A scale-free gene coexpression network was constructed from 360 differentially expressed genes between VAT samples from patients with and without obesity (absolute log fold change > 1, false discovery rate [FDR] < 0.05), with edge probability > 0.8. Gene regulatory network analysis identified candidate transcription factors associated with differentially expressed genes. A total of 15 subnetworks (communities) displayed altered connectivity patterns between obesity and nonobesity networks. Genes in proinflammatory pathways showed increased network connectivity in VAT samples with obesity, whereas the oxidative phosphorylation pathway displayed reduced connectivity (enrichment FDR < 0.05). Functional screening via RNA interference identified genes such as SOX30, SIRPB1, and OSBPL3 as potential network-derived candidates influencing adipocyte differentiation.
Conclusions:
This approach highlights the network architecture in human obesity, identifies novel candidate genes, and generates new hypotheses regarding network-assisted gene regulation in VAT.
