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

Transcription factors (TFs) play a key role in regulating gene expression and responses to stimuli. We conducted an integrated analysis of chromatin accessibility, DNA methylation, and RNA expression across eight rat tissues following endurance exercise training (EET) to map epigenomic changes to transcriptional changes and determine key TFs involved. We uncovered tissue-specific changes and TF motif enrichment across all omic layers, differentially accessible regions (DARs), differentially methylated regions (DMRs), and differentially expressed genes (DEGs). We discovered distinct routes of EET-induced regulation through either epigenomic alterations providing better access for TFs to affect target genes, or via changes in TF expression or activity enabling target gene response. We identified TF motifs enriched among correlated epigenomic and transcriptomic alterations, DEGs correlated with exercise-related phenotypic changes, and EET-induced activity changes of TFs enriched for DEGs among their gene targets. This analysis elucidates the unique transcriptional regulatory mechanisms mediating diverse organ effects of EET. ### Competing Interest Statement S.C.B. has equity in Emmyon, Inc and receives grant funding from Calico Life Sciences. M.P.S. is a cofounder and scientific advisor of Personalis, Qbio, January AI, Filtricine, SensOmics, Protos, Fodsel, Rthm, Marble and scientific advisor of Genapsys, Swaz, Jupiter. S.B.M. is a consultant for BioMarin, MyOme and Tenaya Therapeutics. * HEART : Heart SKM-GN : Skeletal muscle (Gastrocnemius) WAT-SC : Subcutaneous white adipose tissue BAT : Brown adipose tissue LIVER : Liver LUNG : Lung KIDNEY : Kidney HIPPOC : Hippocampus EET : Endurance Exercise Training DAR : Differentially accessible regions DEG : Differentially expressed genes DEGaP : Differentially expressed gene associated peak TSS : Transcription start site TES : Transcription end site TF : Transcription factor