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SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma

Nature Genetics volume 54, pages 861–873 (2022)Cite this article

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Abstract

Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes establish and maintain chromatin accessibility and gene expression, and are frequently perturbed in cancer. Clear cell meningioma (CCM), an aggressive tumor of the central nervous system, is uniformly driven by loss of SMARCE1, an integral subunit of the mSWI/SNF core. Here, we identify a structural role for SMARCE1 in selectively stabilizing the canonical BAF (cBAF) complex core–ATPase module interaction. In CCM, cBAF complexes fail to stabilize on chromatin, reducing enhancer accessibility, and residual core module components increase the formation of BRD9-containing non-canonical BAF (ncBAF) complexes. Combined attenuation of cBAF function and increased ncBAF complex activity generates the CCM-specific gene expression signature, which is distinct from that of NF2-mutated meningiomas. Importantly, SMARCE1-deficient cells exhibit heightened sensitivity to small-molecule inhibition of ncBAF complexes. These data inform the function of a previously elusive SWI/SNF subunit and suggest potential therapeutic approaches for intractable SMARCE1-deficient CCM tumors.

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Fig. 1: SMARCE1 deletion, associated with ~100% of CCM, selectively impacts the stability of cBAF complexes.
Fig. 2: SMARCE1 interactions and structural conformation underlie cBAF-specific functions.
Fig. 3: SMARCE1 loss reduces cBAF occupancy and DNA accessibility over distal enhancer sites genome-wide.
Fig. 4: SMARCE1 loss alters transcriptome in SMARCE1-deficient AC7 cells and in CCM tumors.
Fig. 5: SMARCE1 loss increases ncBAF occupancy and DNA accessibility over enhancer sites genome-wide.
Fig. 6: SMARCE1 loss results in increased biochemical nucleation of ncBAF complexes.
Fig. 7: Small-molecule inhibition of ncBAF complexes attenuates oncogenic gene expression and proliferation of SMARCE1-deficient cells.

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Data availability

All genomic data contained in this manuscript have been deposited on the Gene Expression Omnibus (GEO) repository, https://www.ncbi.nlm.nih.gov/geo/, under accession code GSE174360. Source data are provided with this paper or are provided as Supplementary Information. Raw sequencing data from the fresh-frozen primary meningioma tumor samples (controlled access samples) can be made available upon request to C. Kadoch and D. Meredith, with a time frame for response of 1–2 days, and data availability within 2–3 weeks.

Code availability

No custom code was generated for this study.

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Acknowledgements

We thank all members of the Kadoch laboratory for thoughtful discussions throughout the duration of this project. We are grateful to Z. Herbert and M. Sullivan of the DFCI Molecular Biology Core Facility (MBCF) for help with high-throughput sequencing studies. We are grateful to M. Leidl for technical assistance in SMARCE1 cloning and biochemical experiments. We thank N. Gray for the synthesis and scale-up of dBRD9A. This study was supported in part by the Landry Cancer Consortium Award (R.S.P.), the National Institutes of Health 5F31CA228441-02 (R.S.P.), grants 1DP2CA195762-01 (C.K.), the Pew-Stewart Scholars in Cancer Research Award (C.K.), American Brain Tumor Association (ABTA), the American Cancer Society Research Scholar Award RSG-14-051-01-DMC (C.K.), the all-Manchester National Institute for Health and Care Research (NIHR) Biomedical Research Centre (IS-BRC-1215-20007) (M.J.S.), and the U.S. Army Medical Research Acquisition Activity Congressionally Directed Medical Research Program (USAMRAA CDMRP) Neurofibromatosis Research Program, Investigator-Initiated Research Award (W81XWH1910334) (M.J.S.).

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Author notes

  1. These authors contributed equally: Roodolph St. Pierre, Clayton K. Collings.

Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Roodolph St. Pierre, Clayton K. Collings, Daniel D. Samé Guerra, Christian J. Widmer, Olubusayo Bolonduro, Nazar Mashtalir, Akshay Sankar & Cigall Kadoch

  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Roodolph St. Pierre, Clayton K. Collings, Daniel D. Samé Guerra, Christian J. Widmer, Olubusayo Bolonduro, Nazar Mashtalir, Akshay Sankar & Cigall Kadoch

  3. Chemical Biology Program, Harvard University, Cambridge, MA, USA

    Roodolph St. Pierre

  4. Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Yu Liang & Jun Qi

  5. Department of Neurosurgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Wenya Linda Bi

  6. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    Erica H. Gerkes

  7. Department of Neurology and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Vijaya Ramesh

  8. Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University Hospitals Foundation Trust, Manchester, UK

    Miriam J. Smith

  9. Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, UK

    Miriam J. Smith

  10. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    David M. Meredith

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Contributions

R.S.P., C.J.W. and C.K. conceived of the study. R.S.P. performed all experiments with help from C.J.W., D.D.S.G., O.B. and N.M. All computational analyses were performed by C.K.C., with help from A.S. for cross-linking mass spectrometry and structural analyses. Cmp12 was synthesized and validated by Y.L. with oversight from J.Q., M.J.S., E.H.G., W.L.B. and D.M.M. identified and collected primary tumor and normal human tissue for DNA and RNA sequencing. V.R. provided the AC7 arachnoid cell line, the AC7 NF2-deleted cell line, and guidance for CRISPR–Cas9-mediated editing experiments. C.K. supervised the study. R.S.P., C.K. and C.K.C. wrote and edited the paper.

Corresponding author

Correspondence to Cigall Kadoch.

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Competing interests

C.K. is the scientific founder, Fiduciary Board of Directors member, Scientific Advisory Board member, shareholder and consultant for Foghorn Therapeutics, Inc. (Cambridge, MA). C.K. is also a member of the Scientific Advisory Boards of Nereid Therapeutics and Nested Therapeutics, and serves as a consultant for Cell Signaling Technologies. All other authors do not declare any competing interests.

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Nature Genetics thanks Blaine Bartholomew, Tom Owen-Hughes and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 CCM-associated loss of SMARCE1 selectively impacts the cBAF assembly of mSWI/SNF complexes.

a. Distribution of cranial and spinal SMARCE1-deficient clear cell meningioma reported in the literature; male and female cases indicated in legend. Image adapted from ‘CNS (lateral, no nerves)’, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates. b. Age distribution among SMARCE1-deficient CCM cases (n = 71); median= 10.8 years. c. Frequently mutated genes and their associated pathways in meningioma. SMARCE1 loss uniformly defines the clear cell meningioma subtype. d. Domain architecture and conservation of the human SMARCE1 protein. e. Schematic for SMARCE1 rescue experiments in BT549 SMARCE1-deificient cells. f. Density sedimentation experiments using 10–30% glycerol gradients performed on nuclear extracts isolated from BT549 cells infected with either empty vector control or WT SMARCE1. g. Lentiviral expression of SMARCE1 (or GFP control) in BT549 (SMARCE1 -/-) cells, followed by IP-western blotting for mSWI/SNF complex subunits. *IgG h.c. indicates IgG heavy chain bands are present. (f-g), representative of n = 3 experiments with similar results.

Source data

Extended Data Fig. 2 SMARCE1 has structural homology to ySnf6 and tethers to the initial core of cBAF and PBAF complexes, but to ARID1A and SMARCA4 only in cBAF complexes.

a,b. CX-MS analyses performed on (A) apo human canonical BAF (cBAF), and (B) NCP-bound cBAF complexes. SMARCE1, cBAF-specific subunits (ARID1A and DPF2), and the ATPase subunit, SMARCA4, are shown. c. CX-MS analyses performed on apo human PBAF complexes. SMARCE1, PBAF-specific subunits (ARID2, PBRM1, BRD7 and PHF10), and the ATPase, SMARCA4, are shown. d. Top, Number and distribution of lysine (K) residues (red) on ARID1A/B and ARID2 subunits. Core binding region (CBR) on each is indicated. Bottom, pairwise alignment between ARID1A/B and ARID2 with SMARCE1-ARID1A CX-MS sites highlighted (purple). e. Cross-linking mass spec analyses performed on ySWI/SNF complexes in nucleosome-unbound states [Sen et al., 2017; Mashtalir et al., 2018]. Crosslinks are plotted as a percentage of total crosslinks recovered in the dataset, and are marked by the ySWI/SNF subunit to which they tether (legend). Selected crosslinked lysine (K) residues of Snf6 are labeled. DeepCoil coiled-coil prediction scores are indicated on top row. f. Amino acid sequence conservation of human SMARCE1 to yeast Snf6. g. Human cBAF (PDB: 6LTJ) structure contrasted to cBAF-like yeast SWI/SNF (PDB: 6UXW). h. Cryo-EM structures of ySWI/SNF (PDB: 6UXW) and yRSC (PDB: 6TDA and PDB: 6KW4). Putative SMARCE1 homologs, Snf6 and Htl1, are highlighted in red.

Extended Data Fig. 3 The SMARCE1 subunit in cBAF complexes is required for cBAF-mediated enhancer accessibility.

a. Top, Metaplots over all peaks from Fig. 3b for SMARCE1, SMARCA4, ARID1A, DPF2, ARID2, SS18, H3K27Ac, H3K4me3, and ATAC-seq. Solid line, wild-type AC7 cells; dashed line, SMARCE1 KO cells; Bottom, metaplots over each cluster (clusters 1–3). b. Correlation plots of RNA-seq data between two independent SMARCE1-KO AC7 clones. c. Proliferation of BT549 cells with GFP control or WT SMARCE1 rescue. d. Immunoblot performed on nuclear protein isolated from BT549 cells rescued with control GFP, and wild type SMARCE1. e. Metaplots for ChIP-seq performed on BT549 cells in naive (GFP control infected) or +SMARCE1 conditions (over all peaks from Fig. 3h). f. Stacked bar graph indicating distribution of shared and gained SMARCC1/SMARCA4 peaks upon SMARCE1 rescue in BT549 cells by distance to TSS. g. MA plot reflecting accessibility changes upon SMARCE1 rescue in BT549 cells. h. Stacked bar graph indicating distribution of shared and gained DNA accessibility (ATAC-seq) peaks upon SMARCE1 rescue in BT549 cells by distance to TSS. i. Venn Diagram reflecting overlap between gained SMARCA4/SMARCC1 merged peaks and gained ATAC-seq peaks in BT549 cells in the + SMARCE1 rescue condition. j. Box and whisker plot reflecting gene expression LogFC across sites indicated (gained BAF complex target sites, gained DNA accessibility sites, and BAF/accessibility dually gained sites in BT549 cells with +SMARCE1 rescue. k. Venn diagram of SMARCA4 sites in SMARCE1-KO AC7 cells rescued with either GFP control or WT SMARCE1. l. Heatmap for all merged SMARCA4 sites depicting SMARCE1, SMARCA4, H3K27Ac ChIP-seq, and ATAC-seq in SMARCE1-KO AC7 cells rescued with either GFP control or WT SMARCE1.

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Extended Data Fig. 4 SMARCE1 loss alters transcriptome in SMARCE1-deficient AC7 cells and in clear cell meningioma tumors.

a. MA plot showing gene expression changes upon SMARCE1 loss in AC7 cells. Red and blue dots represent genes significantly upregulated and downregulated, respectively (adj. P < 0.01). b. Motif enrichment analysis by HOMER over sites of BAF occupancy loss in SMARCE1-deficient AC7 cells and of BAF occupancy gain in SMARCE1-deficient cells rescued by WT SMARCE1. c. (Left) Venn diagram reflecting overlap among sites with SMARCA4 loss, sites with accessibility loss, and sites nearest to genes with significant decreases in expression in SMARCE1-deficient AC7 relative to WT (from Cluster 2 in Fig. 3b); (right) Lollipop plot displaying expression of select 55 genes downregulated in AC7 cells that are near sites with decreases in both BAF binding and accessibility. d. Boxplots displaying expression levels of SMARCE1 and NF2 genes in control, SMARCE1-deficient, and NF2-deficient AC7 cells (data from n = 3 biologically-independent cell lines, for normal and SMARCE1-null, and n = 1 cell line for NF2-null; center represents mean, whiskers represent 1.5*IQR, bound of box represent 25th and 75th percentiles for RPKM values). e. Immunoblot performed on nuclear protein isolated from NF2-deficient AC7 clones with associated control; representative of n = 3 experiments with similar results. f. MA plot showing gene expression changes upon NF2 loss in AC7 cells. Red and blue dots represent genes significantly upregulated and downregulated, respectively (adj. P < 0.01). g,h. Gene ontology analysis by Metascape on up and down DEGs (adj. P < 0.01) in SMARCE1-deficient and NF2-deficient AC7 cells relative to the WT condition. i. GSEA results displaying Hallmark MTORC1 Signaling and MYC Targets gene set enrichment for NF2 deficient AC7 cells. j. Volcano plots showing differentially expressed genes in SMARCE1-deficient, NF2-deficient, and KLF/TRAF7-deficient clear cell meningioma tumors relative to normal tissues. Red and blue dots represent genes significantly upregulated and downregulated DEGs, respectively (adj. P < 0.05). k. Venn diagrams reflecting overlap of upregulated and downregulated DEGs for SMARCE1-deficient, NF2-deficient, and KLF/TRAF7-deficient clear cell meningioma tumors relative to normal tissues. l. Heatmap of combined differentially expressed genes from tumor RNA-seq data shown in Fig. 4m. After Z-score transformation, K-means clustering was used to partition the data into 4 groups. m. Gene set enrichment results from hypergeometric tests (using Wikipathway MSIGDB gene set collection) from clusters from Fig. 4g. n. Bar plots displaying gene expression for select genes (FLNA, EBF1, STXBP1, and SKP2) in WT or normal, SMARCE1-deficient, and NF2-deficient AC7 cells and CCM tumors from clusters in Fig. 4g (Mean with error bars representing S.D. are shown for primary tumors, derived from n = />3 biological replicates (samples)).

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Extended Data Fig. 5 Increased biochemical assembly and targeting of ncBAF complexes upon loss of the SMARCE1 subunit.

a. Metaplots for SMARCE1, SMARCA4, SS18, BRD9, H3K27Ac, and ATAC-seq performed over Cluster 3 in Fig. 3b. b. ECDF plots of SMARCA4 Log2 fold change (relative to WT) as a function of motif count for 286 non-redundant transcription factor archetypes motifs over merged BAF peaks in AC7 SMARCE1-KO cells rescued with WT SMARCE1. c. Venn diagrams reflecting (top) all Cut&Tag peaks for BRD9 and SMARCD1 in SMARCE1 WT and KO conditions in AC7 cells; (bottom) Venn diagrams reflecting all ChIP-seq peaks for SMARCA4, ARDI1A, DPF2 in SMARCE1 WT and KO conditions in AC7 cells. d. HOMER motif enrichment performed on Cluster 2 (gained) sites in Fig. 5f. e. Distance to TSS stacked bar graphs corresponding to retained, gained, and lost clusters of SMARCD1 and BRD9 sites identified in Fig. 5f. f. Example tracks at the MS4A7 locus. Tracks for mSWI/SNF subunits, H3K27ac mark, as well as ATAC-seq and RNA-seq tracks are shown.

Extended Data Fig. 6 ncBAF inhibition as synthetic lethal strategy in SMARCE1-deficient clear cell meningioma.

a. Distance to TSS stacked bar graphs for differentially accessible sites (adj P < 0.05) following dBRD9A and CMP12 treatment in SMARCE1-KO and WT AC7 cells. b. Motif enrichment analysis by HOMER over sites with accessibility loss in SMARCE1-deficient AC7 cells after dBRD9A treatment (adj P < 0.05). c. Dose response curves showing CMP12 treatments of WT, SMARCE1-KO, and NF2-KO AC-7 cell lines (n = 2; Mean with SD). d. Proliferation curves for WT and NF2-KO clones treated with 50 nM of CMP12 over the days indicated. Error bars represent S.D. of mean, and p-values derived from two-sided t test are shown (n.s., non-significant), data from n = 3 biologically-independent experiments. e. Stacked bar plots displaying numbers of differentially expressed genes after CMP12 treatment in WT and SMARCE1-deficient AC7 cells. f. (Left) Volcano plot showing differentially expressed genes in SMARCE1-deficient AC7 cells after CMP12 treatment relative to DMSO. Blue dots represent genes with significantly downregulated DEGs (adj. P < 0.01) and purple dots represent downregulated genes that map to sites with accessibility loss in the SMARCE1-deficient cells but not WT cells after dBRD9A treatment. (Right) Pie chart characterizes the distribution of downregulated genes in the SMARCE1-deficient cells after dBRD9A treatment. g. PCA Analysis of ATAC-seq data over merged ATAC-seq peaks for dBRD9A (top) and CMP12 (bottom) treatment in WT and SMARCE1-deficient AC7 cells. h, i. Cis-regulatory analysis by GREAT on differentially accessible sites after dBRD9A treatment (top) and CMP12 treatment (bottom) in SMARCE1-deficient AC7 cells using Go Biological Process terms. j. Bar plots displaying numbers of differentially expressed genes after CMP12 treatment in WT and SMARCE1-deficient AC7 cells at three concentrations relative to changes between WT and SMARCE1-deficient cells in the DMSO condition. k. Venn diagrams show the overlap of upregulated and downregulated DEGs between KO and WT conditions at three concentrations relative to the differences between the KO and WT in the DMSO condition. l. GSEA results showing gene set enrichment (using Hallmark MSIGDB gene set collection) for the KO vs. WT in DMSO comparison and across 3 concentrations of CMP12. m. (left) Venn diagram highlighting downregulated DEGs after dBRD9A/CMP12 treatment (union) in SMARCE1-deficient cells that are not downregulated in WT cells. (Right) Gene ontology analysis performed on genes downregulated following dBRD9A/CMP12 treatment (union) in SMARCE1-KO but not WT cells. n. (Left) Venn diagram highlighting upregulated DEGs after dBRD9A/CMP12 treatment (union) in SMARCE1-deficient cells that are not upregulated in WT cells. (Right) Gene ontology analysis performed on DEGs in red shaded region of Venn diagram on left. o. Expression of top most variable genes reversed in expression by both CMP12 and dBRD9A treatments in SMARCE1-KO cells.

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Supplementary information

Reporting Summary

Supplementary Tables

Supplementary Table 1. SMARCE1-mutant clear cell meningoma cases from the literature. Supplementary Table 2. mSWI/SNF cross-linking mass spectrometry data and calculations. Supplementary Table 3. Details of primary meningioma and normal meninges samples used in this study. Supplementary Table 4. Antibody information.

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St. Pierre, R., Collings, C.K., Samé Guerra, D.D. et al. SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma. Nat Genet 54, 861–873 (2022). https://doi.org/10.1038/s41588-022-01077-0

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