Multiomic 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 and RNA expression across various rat tissues following endurance exercise training (EET) to map epigenomic changes to transcriptional changes and determine key TFs involved. We uncovered tissue-specific changes across both omic layers, including highly correlated differentially accessible regions (DARs) and differentially expressed genes (DEGs). We identified open chromatin regions associated with DEGs (DEGaPs) and found tissue-specific and genomic feature-specific TF motif enrichment patterns among both DARs and DEGaPs. Accessible promoters of up-vs. down-regulated DEGs per tissue showed distinct TF enrichment patterns. Further, some EET-induced TFs in skeletal muscle were either validated at the proteomic level (MEF2C and NUR77) or correlated with exercise-related phenotypic changes. We provide an in-depth analysis of the epigenetic and trans-factor-dependent processes governing gene expression during 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 peaks TSS : Transcription start site TES : Transcription end site TF : Transcription factor