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

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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

How steroid hormone receptors (SHRs) regulate transcriptional activity remains partly understood. Upon activation, SHRs bind the genome together with a co-regulator repertoire, 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 functionally dissected the Glucocorticoid Receptor (GR) complex. We describe a functional cross-talk between PAXIP1 and the cohesin subunit STAG2, 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 chromatin, its localization to GR-occupied sites, and maintenance of enhancer-promoter interactions. 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.

Original languageEnglish
Pages (from-to)9576-9593
Number of pages18
JournalNucleic Acids Research
Volume51
Issue number18
DOIs
Publication statusPublished - 13 Oct 2023

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