RNA binding by the glucocorticoid receptor attenuates dexamethasone-induced gene activation

Sci Rep. 2023 Jun 9;13(1):9385. doi: 10.1038/s41598-023-35549-y.

Abstract

The glucocorticoid receptor (GR) is a ligand-activated transcription factor that regulates a suite of genes through direct binding of GR to specific DNA promoter elements. GR also interacts with RNA, but the function of this RNA-binding activity remains elusive. Current models speculate that RNA could repress the transcriptional activity of GR. To investigate the function of the GR-RNA interaction on GR's transcriptional activity, we generated cells that stably express a mutant of GR with reduced RNA binding affinity and treated the cells with the GR agonist dexamethasone. Changes in the dexamethasone-driven transcriptome were quantified using 4-thiouridine labeling of RNAs followed by high-throughput sequencing. We find that while many genes are unaffected, GR-RNA binding is repressive for specific subsets of genes in both dexamethasone-dependent and independent contexts. Genes that are dexamethasone-dependent are activated directly by chromatin-bound GR, suggesting a competition-based repression mechanism in which increasing local concentrations of RNA may compete with DNA for binding to GR at sites of transcription. Unexpectedly, genes that are dexamethasone-independent instead display a localization to specific chromosomal regions, which points to changes in chromatin accessibility or architecture. These results show that RNA binding plays a fundamental role in regulating GR function and highlights potential functions for transcription factor-RNA interactions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Chromatin
  • DNA / metabolism
  • Dexamethasone* / metabolism
  • Dexamethasone* / pharmacology
  • Glucocorticoids / pharmacology
  • RNA
  • Receptors, Glucocorticoid* / metabolism
  • Transcription Factors / metabolism
  • Transcriptional Activation

Substances

  • Receptors, Glucocorticoid
  • Dexamethasone
  • Transcription Factors
  • Glucocorticoids
  • Chromatin
  • DNA
  • RNA