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PAXIP1 and STAG2 converge to maintain 3D genome architecture and facilitate promoter/enhancer contacts to enable stress hormone-dependent transcription

Authors :
Isabel Mayayo-Peralta
Sebastian Gregoricchio
Karianne Schuurman
Selçuk Yavuz
Anniek Zaalberg
Aleksandar Kojic
Nina Abbott
Bart Geverts
Suzanne Beerthuijzen
Joseph Siefert
Tesa M Severson
Martijn van Baalen
Liesbeth Hoekman
Cor Lieftink
Maarten Altelaar
Roderick L Beijersbergen
Adriaan B Houtsmuller
Stefan Prekovic
Wilbert Zwart
Source :
Nucleic Acids Research.
Publication Year :
2023
Publisher :
Oxford University Press (OUP), 2023.

Abstract

How steroid hormone receptors (SHRs) orchestrate transcriptional activity remains only partly understood. Upon activation, SHRs bind the genome and recruit their co-regulators, crucial to induce gene expression. However, it remains unknown which components of the SHR-recruited co-regulator complex are essential to drive transcription following hormonal stimuli. Through a FACS-based genome-wide CRISPR screen, we comprehensively dissected the Glucocorticoid Receptor (GR) co-regulatory complex involved in gene-target regulation. We describe a novel functional cross-talk between PAXIP1 and the cohesin subunit STAG2 that is critical for regulation of gene expression by GR. Without altering the GR cistrome, PAXIP1 and STAG2 depletion alter the GR transcriptome, by impairing the recruitment of 3D-genome organization proteins to the GR complex. Importantly, we demonstrate that PAXIP1 is required for stability of cohesin on the genome, its localization to GR-occupied sites, and maintenance of enhancer-promoter interactions. Moreover, in lung cancer, where GR acts as tumor suppressor, PAXIP1/STAG2 loss enhances GR-mediated tumor suppressor activity by modifying local chromatin interactions. All together, we introduce PAXIP1 and STAG2 as novel co-regulators of GR, required to maintain 3D-genome architecture and drive the GR transcriptional programme following hormonal stimuli.

Subjects

Subjects :
Genetics

Details

ISSN :
13624962 and 03051048
Database :
OpenAIRE
Journal :
Nucleic Acids Research
Accession number :
edsair.doi.dedup.....e11fe1f74e2cb2daa6028689b386aec3
Full Text :
https://doi.org/10.1093/nar/gkad267