Abstract
Glucocorticoids are stress hormones that elicit cellular responses by binding to the glucocorticoid receptor, 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 1 d. 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 except for one 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.
Highlights
Transcriptional memory is an adaptive strategy that allows cells to “learn” from a previous transient exposure to an environmental stimulus and orchestrate a more efficient response when the same cue is encountered again
Direct DNA binding by glucocorticoid receptor (GR), for example, to AP-1 response elements, and the recruitment of corepressors such as NCOA2 is linked to the transcriptional repression of associated genes [18, 19, 20]
In agreement with previous studies [29, 30, 31, 32], many sites showed an increase in chromatin accessibility (“opening sites” for both hormone treatments when compared with the control treatment [Figs 1A and B and S1A])
Summary
Transcriptional memory is an adaptive strategy that allows cells to “learn” from a previous transient exposure to an environmental stimulus and orchestrate a more efficient response when the same cue is encountered again. Transcriptional memory has been well-studied in plants that have evolved adaptive transcriptional responses to cope with the various environmental stressors they are subjected to and cannot run away from (reviewed in references 2 and 3). It has been described in other systems, such as responses in yeast to environmental signals [4, 5] and the response of cells of the immune system to cytokines [6]. These studies argue that transcriptional repression might be driven by the redistribution of the binding of other transcription factors and coregulators and by alternation of the chromatin structure at enhancers that are not directly occupied by GR [21, 22, 23, 24]
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