Transcription Factors and ncRNAs Associated with CYP3A Expression in Human Liver and Small Intestine Assessed with Weighted Gene Co-Expression Network Analysis.

CYP3A4, CYP3A5, and CYP3A7, which are located in a multigene locus (), play crucial roles in drug metabolism. To understand the highly variable hepatic expression of CYP3As, regulatory network analyses have focused on transcription factors (TFs). Since long non-coding RNAs (lncRNAs) likely contribute to such networks, we assessed the regulatory effects of both TFs and lncRNAs on expression in the human liver and small intestine, main organs of CYP3A expression. Using weighted gene co-expression network analysis (WGCNA) of GTEx v8 RNA expression data and multiple stepwise regression analysis, we constructed TF-lncRNA- co-expression networks. Multiple lncRNAs and TFs displayed robust associations with expression that differed between liver and small intestines (LINC02499, HNF4A-AS1, AC027682.6, LOC102724153, and RP11-503C24.6), indicating that lncRNAs contribute to variance in expression in both organs. Of these, HNF4A-AS1 had been experimentally demonstrated to affect expression. Incorporating ncRNAs into expression regulatory network revealed additional candidate TFs associated with expression. These results serve as a guide for experimental studies on lncRNA-TF regulation of expression in the liver and small intestines.