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

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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.
TidsskriftGenome Research
Udgave nummer3
Sider (fra-til)332-345
Antal sider14
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We thank Jesper Svejstrup, Chirag Nepal, Adrija Kalvisa, Faizaan Mohammad, and Kristian Helin for critical comments on this manuscript and Joachim Weischenfeldt for suggestions regarding patient data analysis. This work was supported through a grant from the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; grant number NNF17CC0027852).

Publisher Copyright:
© 2023 Pundhir et al.; Published by Cold Spring Harbor Laboratory Press.

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