Background: Transcription Factors (TFs) control actuation of genes in the genome and are
key mediators of complex processes such as obesity. Master Regulators (MRs) are the genes at the top
of a regulation hierarchy which regulate other genes.
Objective: To elucidate clusters of highly co-expressed TFs (modules), involved pathways, highly interconnected
TFs (hub-TFs) and MRs leading to obesity and leanness, using porcine model for human
Methods: We identified 817 expressed TFs in RNA-Sequencing dataset representing extreme degrees
of obesity (DO; lean, obese). We built a single Weighted Transcription Factor Co-expression Network
(WTFCN) and TF sub-networks (based on the DO). Hub-TFs and MRs (using iRegulon) were identified
in biologically relevant WTFCNs modules.
Results: Single WTFCN detected the Red module significantly associated with DO (P < 0.03). This
module was enriched for regulation processes in the immune system, e.g.: Immune system process
(Padj = 2.50E-06) and metabolic lifestyle disorders, e.g. Circadian rhythm - mammal pathway (Padj =
2.33E-11). Detected MR, hub-TF SPI1 was involved in obesity, immunity and osteoporosis. Within
the obese sub-network, the Red module suggested possible associations with immunity, e.g. TGF-beta
signaling pathway (Padj = 1.73E-02) and osteoporosis, e.g. Osteoclast differentiation (Padj = 1.94E-
02). Within the lean sub-network, the Magenta module displayed associations with type 2 diabetes,
obesity and osteoporosis e.g. Notch signaling pathway (Padj = 2.40E-03), osteoporosis e.g. hub-TF
VDR (a prime candidate gene for osteoporosis).
Conclusion: Our results provide insights into the regulatory network of TFs and biologically relevant
hub TFs in obesity.