Glucocorticoid-dependence and independence of the circadian liver transcriptome

The liver, a critical metabolic organ, shows clear day-night variation in patterns of gene and protein expression, and in metabolic pathway activity. Liver cells possess molecular circadian clocks, but systemic factors also contribute to the circadian rhythmicity of liver gene expression. Here, we examine the role of glucocorticoid signalling. Glucocorticoids are essential hormones, with a strong circadian oscillation, which control multiple cellular processes via their action on the glucocorticoid receptor (GR). We first compare clock factor and GR binding at promoters and enhancers linked to rhythmic genes, and find increased clock factor binding at those elements where GR is also present. We find that genes with GR binding at the promoter are more likely to show rhythmic expression. We go to test the role of GR more directly, by examining circadian rhythms of gene expression in mice with and without hepatocyte-targeted GR deletion. Notably, we observe only a small effect of GR deletion, with the vast majority of rhythmic genes showing unchanged rhythmic expression, despite evidence for GR binding in the vicinity of these genes. We do find a small number of genes to show lost or gained rhythmicity with GR deletion, and genes which lose rhythmicity do associate with GR binding sites. However, GR appears redundant for conveying timing information to most of the rhythmic liver transcriptome, a conclusion which is supported by our re-analysis of an independent published dataset.