2. Academic Validation
  3. The impact of SWI/SNF and NuRD inactivation on gene expression is tightly coupled with levels of RNA polymerase II occupancy at promoters

The impact of SWI/SNF and NuRD inactivation on gene expression is tightly coupled with levels of RNA polymerase II occupancy at promoters

  • Genome Res. 2023 Mar 16. doi: 10.1101/gr.277089.122.
Sachin Pundhir # 1 2 3,  Jinyu Su # 4 2 3,  Marta Tapia 4 2 3,  Anne Meldgaard Hansen 4 2 3,  James Seymour Haile 4 2 3,  Klaus Hansen 4 2 3,  Bo Torben Porse 1 2 3
Affiliations

Affiliations

  • 1 The Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, DK2200 Copenhagen, Denmark; bo.porse@finsenlab.dk sachin.pundhir@finsenlab.dk.
  • 2 Biotech Research and Innovation Center, Faculty of Health Sciences, University of Copenhagen, DK2200 Copenhagen, Denmark.
  • 3 Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, Faculty of Health Sciences, University of Copenhagen, DK2200 Copenhagen, Denmark.
  • 4 The Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, DK2200 Copenhagen, Denmark.
  • # Contributed equally.
PMID: 36927987 DOI: 10.1101/gr.277089.122
Abstract

SWI/SNF and NuRD are protein complexes that antagonistically regulate DNA accessibility. However, repression of their activities often leads to unanticipated changes in target gene expression (paradoxical), highlighting our incomplete understanding of their activities. Here we show that SWI/SNF and NuRD are in a tug-of-war to regulate PRC2 occupancy at lowly expressed and bivalent genes in mouse embryonic stem cells (mESCs). In contrast, at promoters of average or highly expressed genes, SWI/SNF and NuRD antagonistically modulate RNA polymerase II (Pol II) release kinetics, arguably owing to accompanying alterations in H3.3 and H2A.Z levels at promoter-flanking nucleosomes, leading to paradoxical changes in gene expression. Owing to this mechanism, the relative activities of the two remodelers potentiate gene promoters toward Pol II-dependent open or PRC2-dependent closed chromatin states. Our results highlight RNA Pol II occupancy as the key parameter in determining the direction of gene expression changes in response to SWI/SNF and NuRD inactivation at gene promoters in mESCs.

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