Glucocorticoid stimulation induces regionalized gene responses within topologically associating domains

Frontiers in Genetics

Genetics

Maxime C. Côté¹  Michèle Fournier¹  Maruhen A. D. Silveira¹  Fatemeh Khadangi¹  Félix-Antoine Bérubé-Simard¹  Christophe Tav²  Éric Fournier²  Steve Bilodeau³  Arnaud Droit⁴  Audrey Baguette⁵  Guillaume Bourque⁶ 

[1] Centre de Recherche du CHU de Québec—Université Laval, Axe Oncologie, Québec, QC, Canada;Centre de Recherche sur le Cancer de l’Université Laval, Québec, QC, Canada;Centre de Recherche du CHU de Québec—Université Laval, Axe Oncologie, Québec, QC, Canada;Centre de Recherche sur le Cancer de l’Université Laval, Québec, QC, Canada;Centre de Recherche en Données Massives de l’Université Laval, Québec, QC, Canada;Centre de Recherche du CHU de Québec—Université Laval, Axe Oncologie, Québec, QC, Canada;Centre de Recherche sur le Cancer de l’Université Laval, Québec, QC, Canada;Centre de Recherche en Données Massives de l’Université Laval, Québec, QC, Canada;Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Faculté de Médecine, Université Laval, Québec, QC, Canada;Centre de Recherche sur le Cancer de l’Université Laval, Québec, QC, Canada;Centre de Recherche en Données Massives de l’Université Laval, Québec, QC, Canada;Centre de Recherche du CHU de Québec—Université Laval, Axe Endocrinologie et Néphrologie, Québec, QC, Canada;Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, QC, Canada;Department of Human Genetics, Faculty of Medicine, McGill University, Montréal, QC, Canada;Department of Human Genetics, Faculty of Medicine, McGill University, Montréal, QC, Canada;Canadian Center for Computational Genomics, McGill University, Montréal, QC, Canada;

关键词: transcription;    position effects;    coregulators;    topologically associating domains;    glucocorticoid receptor;   

DOI  :  10.3389/fgene.2023.1237092

 received in 2023-06-08, accepted in 2023-07-07,  发布年份 2023

来源: Frontiers

【 摘 要 】

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 glucocorticoid stimulation led to the reorganization of transcriptional coregulators MED1 and BRD4 within topologically associating domains (TADs), resulting in active or repressive gene environments. Indeed, we observed a bias toward the activation or repression of a TAD when their activities were defined by the number of regions gaining and losing MED1 and BRD4 following 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 the differential recruitment of MED1 and BRD4 or binding by the glucocorticoid receptor 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 the response of Dex-regulated genes was higher when the differential recruitment of the glucocorticoid receptor 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.

【 授权许可】

Unknown   
Copyright © 2023 Tav, Fournier, Fournier, Khadangi, Baguette, Côté, Silveira, Bérubé-Simard, Bourque, Droit and Bilodeau.