Mammalian SWI/SNF continuously restores local accessibility to chromatin

Mario Iurlaro; Michael B Stadler; Francesca Masoni; Zainab Jagani; Giorgio G Galli; Dirk Schübeler

doi:10.1038/s41588-020-00768-w

Mammalian SWI/SNF continuously restores local accessibility to chromatin

Nat Genet. 2021 Mar;53(3):279-287. doi: 10.1038/s41588-020-00768-w. Epub 2021 Feb 8.

Authors

Mario Iurlaro¹, Michael B Stadler^{1

2

3}, Francesca Masoni^{1

3}, Zainab Jagani⁴, Giorgio G Galli⁵, Dirk Schübeler^{6

7}

Affiliations

¹ Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
² Swiss Institute of Bioinformatics, Basel, Switzerland.
³ Faculty of Science, University of Basel, Basel, Switzerland.
⁴ Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
⁵ Novartis Institutes for Biomedical Research, Basel, Switzerland.
⁶ Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. dirk@fmi.ch.
⁷ Faculty of Science, University of Basel, Basel, Switzerland. dirk@fmi.ch.

PMID: 33558757
DOI: 10.1038/s41588-020-00768-w

Abstract

Chromatin accessibility is a hallmark of regulatory regions, entails transcription factor (TF) binding and requires nucleosomal reorganization. However, it remains unclear how dynamic this process is. In the present study, we use small-molecule inhibition of the catalytic subunit of the mouse SWI/SNF remodeler complex to show that accessibility and reduced nucleosome presence at TF-binding sites rely on persistent activity of nucleosome remodelers. Within minutes of remodeler inhibition, accessibility and TF binding decrease. Although this is irrespective of TF function, we show that the activating TF OCT4 (POU5F1) exhibits a faster response than the repressive TF REST. Accessibility, nucleosome depletion and gene expression are rapidly restored on inhibitor removal, suggesting that accessible chromatin is regenerated continuously and in a largely cell-autonomous fashion. We postulate that TF binding to chromatin and remodeler-mediated nucleosomal removal do not represent a stable situation, but instead accessible chromatin reflects an average of a dynamic process under continued renewal.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATPases Associated with Diverse Cellular Activities / genetics
ATPases Associated with Diverse Cellular Activities / metabolism
Adenosine Triphosphatases / genetics
Adenosine Triphosphatases / metabolism
Animals
Binding Sites
Cell Line / drug effects
Chromatin / genetics
Chromatin / metabolism*
Chromatin Assembly and Disassembly / drug effects
Chromatin Assembly and Disassembly / physiology
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism
DNA Helicases / antagonists & inhibitors
DNA Helicases / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Gene Expression Regulation / drug effects
Histones / genetics
Histones / metabolism
Mice
Mouse Embryonic Stem Cells / cytology
Mouse Embryonic Stem Cells / drug effects
Multiprotein Complexes / drug effects
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism*
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / metabolism
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
Receptors, Estrogen / genetics
Receptors, Estrogen / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Small Molecule Libraries / pharmacology
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

Chromatin
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Esrrb protein, mouse
Histones
Multiprotein Complexes
Nuclear Proteins
Octamer Transcription Factor-3
Pou5f1 protein, mouse
RE1-silencing transcription factor
Receptors, Estrogen
Repressor Proteins
Small Molecule Libraries
Transcription Factors
Adenosine Triphosphatases
Smarca4 protein, mouse
Smarca5 protein, mouse
ATPases Associated with Diverse Cellular Activities
DNA Helicases
INO80 protein, mouse