Multi-omic identification of key transcriptional regulatory programs during endurance exercise training in rats

Transcription factors play a key role in regulating gene expression. We conduct an integrated analysis of chromatin accessibility, DNA methylation, mRNA expression, protein abundance and phosphorylation across eight tissues in fifty rats of equally represented sexes following endurance exercise training to identify coordinated epigenomic and transcriptional changes and determine key transcription factors involved. We uncover tissue-specific endurance exercise training associated changes and transcription factor motif enrichment across differentially expressed genes, accessible regions, and methylated regions. We discover distinct routes of training-induced regulation through either epigenomic alterations providing better access for transcription factors to affect target genes, or via changes in transcription factor expression or activity enabling target gene responses. We identify transcription factor motifs enriched among correlated epigenomic and transcriptomic alterations, differentially expressed genes correlated with exercise-related phenotypic and cell type composition changes, and training-induced activity changes of transcription factors whose target genes are enriched for differentially expressed genes. This analysis elucidates the unique gene regulatory mechanisms mediating diverse transcriptional responses to training across tissues.