Methionine Deprivation-induced Reprogramming of Hepatic Rhythms Is Mediated by Glucocorticoid Receptor

Abstract

The circadian clock tightly interacts with cellular metabolism, and nutritional challenges can profoundly remodel its function. Dietary methionine restriction has been shown to improve metabolic health and extend lifespan. However, whether and how dietary methionine restriction impacts the circadian clock is unclear. Here, we demonstrate that methionine deprivation (MD) in the mouse induces alterations in multiple signaling systems, inducing rhythmic biological events in liver that are entrained by feeding time rather than day/light cycles. Alteration in growth factor signaling leads to loss of activation of a pioneer transcription factor, STAT5, which normally directs rhythmic chromatin localization of the glucocorticoid receptor (GR). Loss of active STAT5 leads to reprogramming of the epigenome and of the GR-directed transcriptome in a manner abolished by liver-specific deletion of GR. These results demonstrate that dietary methionine restriction remodels the circadian biological program directed by glucocorticoid receptor.