Construction and analyzing integrated gene regulatory network:
The data of transcription factors (TF)-binding site were obtained from the ChIP Enrichment analysis (ChEA) database (Chen et al., 2013; Kuleshov et al., 2016).ChEA contains TF-DNA interactions data obtained from ChIP-chip, ChIP-seq, ChIP-PET, and DamID (Chen et al., 2013; Kuleshov et al., 2016). We perused the DEGs list in this database and retrieved TFs that controlled the expression of DEGs and kept TFs that contained p-value  < 0.05. In the case of TFs, instead of our criteria to find DEGs (log2 fold change >1) as a common fold change, we set another level of filtering to identify differentially expressed TFs (DE-TFs) by setting expression fold change to 1.5 and selecting those as DE-TFs. Using TF-binding site data of the DE-TFs, DE-TF expression, and DEGs, the GRNs were constructed in the Cytoscape software. The most central TFs which regulate majority of the downregulated genes were identified using CentisCape plugin of the Cytoscape (Scardoni, Petterlini, & Laudanna, 2009). This plugin considers the direct interaction of the TFs with their targets as parameter called degree. Those TFs with highest number of target genes will be considered as the most central TFs.