Glucocorticoid-dependence and independence of the circadian liver transcriptome

The liver, a key metabolic organ, shows clear day-night variation in gene and protein expression, and in metabolic pathway activity. Liver cells possess molecular circadian clocks, but systemic factors are critical contributors to the circadian rhythmicity of liver gene expression. Glucocorticoid action is reported to be one such factor. Glucocorticoids are essential hormones, with strong circadian oscillations, which control multiple cellular processes via the glucocorticoid receptor (GR). We compare clock factor and GR binding at promoters and enhancers linked to rhythmic genes and find increased clock factor binding at those promoter elements where GR is also present. Genes with GR binding at the promoter are more highly expressed and more likely to be detected as rhythmic. We then test the role of GR directly, by profiling rhythmic gene expression in mice with/without hepatocyte-targeted GR deletion. Notably, we observe only a small effect of GR deletion, with most rhythmic genes showing unchanged rhythmicity, despite evidence for local GR binding. We find a small number of genes showing lost or gained rhythmicity with GR deletion; genes which lose rhythmicity associate with GR binding sites. Contrary to expectations, GR appears redundant for conveying timing information to most of the rhythmic liver transcriptome.