Molecular mechanisms of the transcriptional regulation by PGC-1α/β in skeletal muscle

Skeletal muscle (SKM) is an energetic organ with a high degree of plasticity. Different environmental stimuli as exercise or cold, but also physical inactivity, lead to complex molecular regulations that result in metabolic adaptations of the SKM and the whole body. Key factors in SKM plasticity and whole body energy homeostasis are the peroxisome proliferator-activated receptor (PPAR) γ coactivator-1 (PGC-1) family including three members, PGC-1α, PGC-1β and PGC-related coactivator (PRC). The PGC-1s are coactivators and hence use transcription factor binding partners (TFBP) in order to regulate their target genes. The complexity of transcriptional control might even be increased by epigenetic alterations, mainly DNA methylation. The aim of my thesis was to study the regulation of global molecular mechanisms by SKM PGC-1α and PGC-1β leading to muscle plasticity in various environmental contexts. We combined diverse experimental, computational and multi-omics approaches such as chromatin immunoprecipitation sequencing (ChIPseq), RNA sequencing (RNAseq), reduced representation bisulfite sequencing (RRBS) and CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR-associated proteins) genome editing technology in skeletal muscle systems in vitro and in vivo and investigated the effect of external stimuli as cold or exercise in different PGC-1α/β genotypes. Our data show that various interventions like acute and chronic exercise have different methylation profiles or combined with cold-induced muscle shivering, individual transcript profiles in wild type (WT) mice. A time-dependent correlation of DNA methylation with gene expression was observed, however dissimilar in acute and chronic exercise. Furthermore, we dissected potential memory marks on the DNA by methylation following chronic training in mice. In addition, we could show for the first time a role of PGC-1α, not only in exercise performance but as well in altered transcriptome and methylome profiles subsequent to exercise and changed ...