Transcriptional and Chromatin Regulation during Fasting - The Genomic Era

An elaborate metabolic response to fasting is orchestrated by the liver and is heavily reliant on transcriptional regulation. In response to hormones (glucagon, glucocorticoids) many transcription factors (TFs) are activated and regulate various genes involved in metabolic pathways aimed at restoring homeostasis: gluconeogenesis, fatty acid oxidation, ketogenesis, and amino acid shuttling. We summarize recent discoveries regarding fasting-related TFs with an emphasis on genome-wide binding patterns. Collectively, the findings we discuss reveal a large degree of cooperation between TFs during fasting that occurs at motif-rich DNA sites bound by a combination of TFs. These new findings implicate transcriptional and chromatin regulation as major determinants of the response to fasting and unravels the complex, multi-TF nature of this response. Many transcription factors (TFs) regulate the various metabolic pathways needed to restore homeostasis on fasting. Recent advances in genome biology have established a genome-wide characterization of TF binding profiles, showing an extensive, genome-wide transcriptional response to fasting and revealing mechanistic insights regarding TF mode of action. There is a large degree of cooperation between TFs during fasting that occurs at motif-rich sites on DNA bound by several fasting-related TFs. Much of this collaboration between factors is achieved through localized opening of restrictive chromatin structures. Fasting initiates transcription cascades wherein TFs regulate the expression of genes encoding other TFs that augment and advance the response to fasting.