AUTHOR=Tav Christophe , Fournier Éric , Fournier Michèle , Khadangi Fatemeh , Baguette Audrey , Côté Maxime C. , Silveira Maruhen A. D. , Bérubé-Simard Félix-Antoine , Bourque Guillaume , Droit Arnaud , Bilodeau Steve 

TITLE=Glucocorticoid stimulation induces regionalized gene responses within topologically associating domains

JOURNAL=Frontiers in Genetics

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1237092

DOI=10.3389/fgene.2023.1237092

ISSN=1664-8021

ABSTRACT=Transcription factor binding to cis-regulatory regions regulates the gene expression program of a cell, but occupancy is often a poor predictor of the gene response. Here we show that a glucocorticoid stimulation led to a reorganization of transcriptional coregulators MED1 and BRD4 within topologically associating domains (TADs), resulting in active or repressive gene environments. Indeed, we observed a bias towards activation or repression of a TAD when their activities were defined by the number of regions gaining and losing MED1 and BRD4 following a dexamethasone (Dex) stimulation. Variations in Dex-responsive genes at the RNA levels were consistent with the redistribution of MED1 and BRD4 at the associated cis-regulatory regions. Interestingly, Dex-responsive genes without differential recruitment of MED1 and BRD4 or binding by the glucocorticoid receptor (GR) were found within TADs which gained or lost MED1 and BRD4 suggesting a role of the surrounding environment in gene regulation. However, the amplitude of response of Dex-regulated genes was higher when differential recruitment of GR and transcriptional coregulators was observed, reaffirming the role of transcription factor-driven gene regulation and attributing a lesser role to the TAD environment. These results support a model where a signal-induced transcription factor induces a regionalized effect throughout the TAD, redefining the notion of direct and indirect effects of transcription factors on target genes.