Glucocorticoid receptor suppresses gene expression of Rev-erbα (Nr1d1) through interaction with the CLOCK complex

FEBS Lett. 2019 Feb;593(4):423-432. doi: 10.1002/1873-3468.13328. Epub 2019 Feb 1.

Abstract

Glucocorticoids have various medical uses but are accompanied by side effects. The glucocorticoid receptor (GR) has been reported to regulate the clock genes, but the underlying mechanisms are incompletely understood. In this study, we focused on the suppressive effect of the GR on the expression of Rev-erbα (Nr1d1), an important component of the clock regulatory circuits. Here we show that the GR suppresses Rev-erbα expression via the formation of a complex with CLOCK and BMAL1, which binds to the E-boxes in the Nr1d1 promoter. In this GR-CLOCK-BMAL1 complex, the GR does not directly bind to DNA, which is referred to as tethering. These findings provide new insights into the role of the GR in the control of circadian rhythm.

Keywords: circadian rhythm; clock; glucocorticoid receptor; glucocorticoids; tethering.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / metabolism*
  • Animals
  • CLOCK Proteins / metabolism*
  • Circadian Rhythm / drug effects
  • Dexamethasone / administration & dosage*
  • Dexamethasone / pharmacology
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Male
  • Mice
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / chemistry
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics*
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism
  • Promoter Regions, Genetic
  • Receptors, Glucocorticoid / agonists
  • Receptors, Glucocorticoid / metabolism*

Substances

  • ARNTL Transcription Factors
  • BMAL1 protein, human
  • NR1D1 protein, human
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Receptors, Glucocorticoid
  • Dexamethasone
  • CLOCK Proteins
  • CLOCK protein, human