Genomic Convergence in Hibernating Mammals Elucidates the Genetics of Metabolic Regulation in the Hypothalamus

Abstract

AbstractElucidating the genetic basis of mammalian metabolism could help define mechanisms central to health and disease. Here, we define conservedcis-regulatory elements (CREs) and programs for mammalian metabolic control. We delineate gene expression and chromatin responses in the mouse hypothalamus for 7 steps of the Fed-to-Fasted-to-Refed (FFR) response process. Comparative genomics of hibernating versus non-hibernating lineages then illuminatescis-elements showing convergent changes in hibernators. Hibernators accumulated loss-of-function effects for specific CREs regulating hypothalamic FFR responses. Multi-omics approaches pinpoint key CREs, genes, regulatory programs, and cell types in the divergence of hibernating and homeothermic lineages. The refeeding period after extended fasting is revealed as one critical period of chromatin remodeling with convergent genomic changes. This genetic framework is a step toward harnessing hibernator adaptations in medicine.One sentence summaryConvergent signals definecis-regulatory mechanisms behind food scarcity responses and hibernator-homeotherm divergence.