Journal Article

Mammalian SWI/SNF continuously restores local accessibility to chromatin

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

2021

Overview

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. Chemical inhibition of the SWI/SNF remodeling complex shows decreased accessibility and transcription factor binding within minutes. These changes are rapidly restored on inhibitor removal suggesting that accessible chromatin is regenerated continuously.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38/39 / 45/15 / 45/23 / 45/41 / 631/208/191 / 631/208/200 / 631/208/212 / 631/208/212/177 / 631/337/176 / Accessibility / Adenosine Triphosphatases - genetics / Adenosine Triphosphatases - metabolism / Agriculture / Animal Genetics and Genomics / Animals / ATPases Associated with Diverse Cellular Activities - genetics / ATPases Associated with Diverse Cellular Activities - metabolism / Binding Sites / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell cycle / Cell division / Cell Line - drug effects / Chromatin / 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 / Datasets / Deoxyribonucleic acid / Depletion / DNA / DNA Helicases - antagonists & inhibitors / DNA Helicases - metabolism / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Enzymes / Experiments / Gene expression / Gene Expression Regulation - drug effects / Gene Function / Genetic aspects / Genomes / Histones - genetics / Histones - metabolism / Human Genetics / Letter / Mammals / 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 / Oct-4 protein / Octamer Transcription Factor-3 - genetics / Octamer Transcription Factor-3 - metabolism / Physiological aspects / Receptors, Estrogen - genetics / Receptors, Estrogen - metabolism / Regulatory sequences / Repressor Proteins - genetics / Repressor Proteins - metabolism / Small Molecule Libraries - pharmacology / Stem cells / Transcription factors / Transcription Factors - antagonists & inhibitors / Transcription Factors - genetics / Transcription Factors - metabolism