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Mammalian SWI/SNF continuously restores local accessibility to chromatin

Nature Genetics volume 53, pages 279–287 (2021)Cite this article

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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.

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Fig. 1: Specificity of SWI/SNF inhibition by BRM014 in mESCs.
Fig. 2: Blocking SWI/SNF activity causes a rapid loss of accessibility that varies among regulatory regions.
Fig. 3: Inhibition of SWI/SNF activity instantly impairs accessibility at Brg1-dependent TF-binding sites.
Fig. 4: Restoring SWI/SNF activity rapidly reinstates the chromatin accessibility landscape.

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Data availability

Next-generation sequencing data reported in this study are available at Gene Expression Omnibus, accession no. GSE158345. Source data are provided with this paper.

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Acknowledgements

We thank L. Burger for feedback and providing lists of TF-bound sites, S. Smallwood and the functional genomics platform of the FMI for next-generation sequencing support, H. Kohler for assistance with cell sorting, and members of the Schübeler group for feedback on the project and manuscript. Research in the laboratory of D.S. is supported by the Novartis Research Foundation, the European Research Council under the European Union’s Horizon research and innovation program (grant no. 667951) and the Swiss National Sciences Foundation. M.I. was supported by a European Molecular Biology Organization long-term postdoctoral fellowship (ALTF 594-2017) and a European Molecular Biology Organization advanced fellowship (ALTF 611-2019).

Author information

Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

    Mario Iurlaro, Michael B. Stadler, Francesca Masoni & Dirk Schübeler

  2. Swiss Institute of Bioinformatics, Basel, Switzerland

    Michael B. Stadler

  3. Faculty of Science, University of Basel, Basel, Switzerland

    Michael B. Stadler, Francesca Masoni & Dirk Schübeler

  4. Novartis Institutes for Biomedical Research, Cambridge, MA, USA

    Zainab Jagani

  5. Novartis Institutes for Biomedical Research, Basel, Switzerland

    Giorgio G. Galli

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Contributions

M.I. and D.S. conceived the study and designed the experiments. M.I. performed the experiments and analyzed the data. M.B.S. performed advanced computational analysis. F.M. contributed to ChIP–seq experiments. G.G.G. and Z.J. provided inhibitor expertise and compounds. D.S. supervised the study. M.I., M.B.S. and D.S. wrote the manuscript with input from all coauthors.

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Correspondence to Dirk Schübeler.

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All the authors affiliated with Novartis Institute of Biomedical Research are employees of Novartis. The remaining authors have no competing interests.

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Peer review information Nature Genetics thanks Blaine Bartholomew, Julie Lessard and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Chromatin accessibility changes caused by BRM014 treatment in mouse ES cells.

a. RNA levels of Brg1 (Smarca4) and Brm (Smarca2) in mouse ES cells. The proteins encoded by these genes are the primary targets inhibited by the BRM014 compound (n = 8, mean + /- sd). b. Schematic of Ino80 deletion induced by CRISPR/Cas9 system, 7-bp deletion in exon6 is highlighted in red characters. Representative western blot (repeated three times) shows cropped bands for resulting full-length Ino80 protein and loading control in WT and deleted line (uncropped blots in Source Data). c. Quantitative comparison of ATAC-seq replicates (log2 normalized counts). d. Quantitative comparison of chromatin accessibility changes (log2 fold-change) at regulatory regions upon chemical inhibition of SWI/SNF ATPase Brg1 at a concentration of 10 µM (x-axis) and 1 µM (y-axis). The effects are dose-dependent and correlated. R: Pearson’s correlation coefficient. e. Same as in d), for treatment with BRM014 at 10 µM for 24 h (x-axis) and an inactive compound at the same concentration (y-axis). Loss of accessibility is specific to the active SWI/SNF inhibitor.

Source data

Extended Data Fig. 2 Gene expression changes caused by BRM014 treatment in mouse ES cells.

a. Quantitative comparison of transcriptional changes (log2 fold-change) induced by BRM014 in different genetic background (wt on both x-axes, Ino80 KO y-axis left panel, Snf2h KO y-axis right panel). b. Quantitative comparison of transcriptional changes (log2 fold-change) induced by BRM014 in wt cells (x-axis, both panel) and changes induced by genetic deletion of Ino80 (left panel) or Snf2h (right panel).

Extended Data Fig. 3 Chromatin type and histone variant H3.3 in groups of ATAC-seq peaks.

a. Line-plots showing changes in chromatin accessibility in the different clusters upon BRM014 treatment over time measured by ATAC-seq. Each line represents a single ATAC peak from a set of 300 peaks randomly selected from each cluster, and their average is drawn as a red line. b. Percent of ATAC-seq peaks in each cluster (1 to 5) or genomic bases (genome) residing in different types of chromatin as determined by ChromHMM. c. Heatmap showing the relative enrichment of grouped ATAC-seq peaks from Fig. 2a in different types of chromatin. Enrichment values correspond to standardized residuals (observed – expected) / sqrt(V), where V is the residual cell variance calculated using the chisq.test function in R. d. Average read densities of Histone H3.3 ChIP-seq reads (top) or input chromatin (bottom) around the middle of grouped ATAC-seq peaks from Fig. 2a (1 to 5), or all ATAC-seq peaks that do not significantly change accessibility upon 24 h of BRM014 (10 µM) treatment compared to DMSO (unchanged, n = 70,450, absolute log2 fold-change < 1.0 or FDR > 0.01).

Extended Data Fig. 4 Gene-ontology enriched terms for genes differentially expressed upon SWI/SNF inhibition.

Barplots showing fold-enrichment for most enriched gene-ontology germs for differentially expressed genes upon 24 h SWI/SNF inhibition, divided into six groups based on direction (up-, down-) and dynamics (early-, middle-, late-) of response.

Extended Data Fig. 5 Enrichment of TF binding motifs in ATAC-seq peaks binned by change of accessibility upon SWI/SNF inhibition.

a. Enrichments ((observed – expected) / sqrt(expected)) and significance (-log10 of FDR) of predicted TF binding sites were calculated in ATAC-seq peaks binned (1200 peaks per bin) according to change of accessibility upon long-term (24 h) SWI/SNF inhibition. TFs with an FDR in the strongest loss bin of less than 1e-8 plus selected TFs (green squares, see below) are shown. The columns of the heatmaps correspond to bins of ATAC-seq peaks, ordered by loss of accessibility and starting on the left with the bin of strongest loss. The TFs shown in Fig. 3 (REST, OCT4/SOX2, ESRRB, CTCF and NRF1) are depicted with a green square next to their name and were included even if their FDR was larger than the selection cutoff. Motifs (heatmap rows) have been hierarchically clustered based on enrichments. b. Same as in a), but ATAC-seq peaks were binned according to change of accessibility upon short (1 h) SWI/SNF inhibition. TFs with an FDR in the strongest-loss bin of less than 1e-4 are shown.

Extended Data Fig. 6 Rapid reversal of SWI/SNF activity after short inhibition.

a. Heatmap displaying changes in chromatin accessibility compared to control cells treated with DMSO at ATAC-seq peaks upon treatment with 10 µM of compound BRM014 for increasing amounts of time and subsequent washout of the inhibitor from the growing media. Washout samples were collected 15, 30 and 60 minutes after removal of the compound. Removal of the inhibitor results in complete reversal of the accessibility landscape. Grouping and order of peaks as in Fig. 2a. b. Exemplary genomic locus showing SWI/SNF-dependent ATAC peak (dotted square) losing signal over time during treatment with BRM014 (red tracks) and total rescue of accessibility upon washout of the compound (blue tracks). c. Chromatin accessibility changes at distal REST, OCT4/SOX2, ESRRB, CTCF and NRF1 binding sites upon SWI/SNF inhibition (10, 20, 30 and 60 minutes in shades of red) and after removal of the inhibitor (15, 30 and 60 minutes in shades of blue). Upper panels: Line plots indicating changes in ATAC signal compared to DMSO control. Vertical dashed line highlights timepoint of inhibitor removal. Lower panels: Average signal over all bound sites in different conditions as above. d. Average MNase signal (fragment midpoints) at bound REST and CTCF motifs in DMSO control cells (black line), after 24 h of BRM014 treatment (red line) and after washout (blue line).

Supplementary information

Source data

Source Data Extended Data Fig. 1

Unprocessed western blot for Ino80 and lamin-loading control (shown in Extended Data Fig. 1) with overlaid marker.

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Iurlaro, M., Stadler, M.B., Masoni, F. et al. Mammalian SWI/SNF continuously restores local accessibility to chromatin. Nat Genet 53, 279–287 (2021). https://doi.org/10.1038/s41588-020-00768-w

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