Ruta Skinkyte-Juskiene, Lisette J.A. Kogelman and Haja N. Kadarmideen* Pages 289 - 299 ( 11 )
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 obesity.
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.
Obesity, Transcription factors, WGCNA, Transcriptomics, RNA-Seq, Gene networks.
Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Grønnegardsvej 7, 1870 Frederiksberg C, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Grønnegardsvej 7, 1870 Frederiksberg C, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Grønnegardsvej 7, 1870 Frederiksberg C