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Glucocorticoid receptor activation induces gene-specific transcriptional memory and universally reversible changes in chromatin accessibility

Melissa Bothe, René Buschow, View ORCID ProfileSebastiaan H. Meijsing
doi: https://doi.org/10.1101/2021.01.05.425406
Melissa Bothe
1Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany
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René Buschow
1Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany
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Sebastiaan H. Meijsing
1Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany
2Max Planck Unit for the Science of Pathogens, Charitéplatz 1, 10117 Berlin, Germany
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  • ORCID record for Sebastiaan H. Meijsing
  • For correspondence: meijsing@mpusp.mpg.de
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Abstract

Glucocorticoids are stress hormones that elicit cellular responses by binding to the glucocorticoid receptor (GR), a ligand-activated transcription factor. The exposure of cells to this hormone induces wide-spread changes in the chromatin landscape and gene expression. Previous studies have suggested that some of these changes are reversible whereas others persist even when the hormone is no longer around. However, when we examined chromatin accessibility in human airway epithelial cells after hormone washout, we found that the hormone-induced changes were universally reversed after one day. Reversibility of hormone-induced changes are found for GR-occupied opening sites and also for closing sites that typically lack GR occupancy. These closing sites are enriched near repressed genes, suggesting that transcriptional repression by GR does not require nearby GR binding. Mirroring what we say in terms of chromatin accessibility, we found that transcriptional responses to hormone are universally reversable. Moreover, priming of cells by a previous exposure to hormone, in general, did not alter the transcriptional response to a subsequent encounter of the same cue. Interestingly, despite the short-lived nature of hormone-induced changes in the chromatin landscape, we identified a single gene, ZBTB16, that displays transcriptional memory manifesting itself as a more robust transcriptional response upon repeated hormone stimulation. Single-cell analysis revealed that the more robust response is driven by a higher probability of primed cells to activate ZBTB16 and by a subset of cells that express the gene at levels that are higher than the induction levels observed for naïve cells. Although our study shows that hormone-induced changes are typically reversable, exposure to hormone can induce gene-specific changes in the response to subsequent exposures which may play a role in habituation to stressors and changes in glucocorticoid sensitivity.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 06, 2021.
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Glucocorticoid receptor activation induces gene-specific transcriptional memory and universally reversible changes in chromatin accessibility
Melissa Bothe, René Buschow, Sebastiaan H. Meijsing
bioRxiv 2021.01.05.425406; doi: https://doi.org/10.1101/2021.01.05.425406
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Glucocorticoid receptor activation induces gene-specific transcriptional memory and universally reversible changes in chromatin accessibility
Melissa Bothe, René Buschow, Sebastiaan H. Meijsing
bioRxiv 2021.01.05.425406; doi: https://doi.org/10.1101/2021.01.05.425406

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