# Glucocorticoid-dependence and independence of the circadian liver transcriptome

## TL;DR

This study explores how the liver's daily gene activity is influenced by internal clocks and glucocorticoid hormones, finding that most genes maintain their rhythm even without glucocorticoid action.

## Contribution

The study reveals that glucocorticoid receptors are not essential for most rhythmic liver gene expression, challenging previous assumptions.

## Key findings

- Most rhythmic liver genes remain rhythmic even when glucocorticoid receptors are deleted in hepatocytes.
- Genes that lose rhythmicity with GR deletion are associated with glucocorticoid receptor binding sites.
- Clock factor binding is increased at promoter regions where glucocorticoid receptors are also present.

## Abstract

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.