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Cooperation of chromatin remodeling SWI/SNF complex and pioneer factor AP-1 shapes 3D enhancer landscapes

Nature Structural & Molecular Biology volume 30, pages 10–21 (2023)Cite this article

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Abstract

The mechanism controlling the dynamic targeting of SWI/SNF has long been postulated to be coordinated by transcription factors (TFs), yet demonstrating a specific TF influence has proven difficult. Here we take a multi-omics approach to interrogate transient SWI/SNF interactors, chromatin targeting and the resulting three-dimensional epigenetic landscape. We utilize the labeling technique TurboID to map the SWI/SNF interactome and identify the activator protein-1 (AP-1) family members as critical interacting partners for SWI/SNF complexes. CUT&RUN profiling demonstrates SWI/SNF targeting enrichment at AP-1 bound loci, as well as SWI/SNF–AP-1 cooperation in chromatin targeting. HiChIP reveals AP-1–SWI/SNF-dependent restructuring of the three-dimensional promoter–enhancer architecture and generation of enhancer hubs. Through interrogation of the SWI/SNF–AP-1 interaction, we demonstrate an SWI/SNF dependency on AP-1-mediated chromatin localization. We propose that pioneer factors, such as AP-1, bind and target SWI/SNF to inactive chromatin, where it restructures the genomic landscape into an active state through epigenetic rewiring spanning multiple dimensions.

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Fig. 1: SWI/SNF interactome via proximity-based labeling.
Fig. 2: Dynamics of SWI/SNF subcomplex targeting.
Fig. 3: SWI/SNF complex interacts with the AP-1 complex and colocalizes on the genome.
Fig. 4: Cooperative targeting between the SWI/SNF complex and AP-1 complex.
Fig. 5: In vivo remodeling activity of the SWI/SNF complex measured by EChO.
Fig. 6: SWI/SNF-complex-mediated 3D enhancer landscapes.

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Data availability

All next-generation sequencing data are available from the Gene Expression Omnibus (GEO) under accession nos. GSE175534 and GSE196960. Source data are provided with this paper.

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Acknowledgements

We thank all members of the Wang laboratory for insightful and helpful discussions. We thank S. Henikoff (Fred Hutchinson Cancer Research Center) for providing the pA/G-MNase fusion protein, M. Meers (Fred Hutchinson Cancer Research Center) for helping with EChO analysis, and X. Zhang (Huntsman Cancer Institute) for helping with HiChIP analysis. This work was supported by the US National Institutes of Health (grants nos. R00CA197640 (X.W.), R01CA259850 (X.W.) and R01GM122846 (S.A.G.)), the Cancer Prevention Research Institute of Texas (CPRIT, RR180061 to C.C.) and a Dartmouth College Norris Cotton Cancer Center Support Grant (P30CA023108).The Andrew McDonough B+ (Be Positive) Foundation provided additional support for X.W. C.C. is a CPRIT Scholar in Cancer Research.

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Author notes

  1. These authors contributed equally: Bennett K. Wolf, Yanding Zhao, Andrew McCray.

Authors and Affiliations

  1. Department of Molecular & Systems Biology, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH, USA

    Bennett K. Wolf, Andrew McCray, William H. Hawk, Luke T. Deary, Nicholas W. Sugiarto, Ian S. LaCroix, Scott A. Gerber & Xiaofeng Wang

  2. Dartmouth Cancer Center, Dartmouth College, Lebanon, NH, USA

    Bennett K. Wolf, Andrew McCray, William H. Hawk, Luke T. Deary, Ian S. LaCroix, Scott A. Gerber & Xiaofeng Wang

  3. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Yanding Zhao & Chao Cheng

  4. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Yanding Zhao & Chao Cheng

  5. Institute for Clinical and Translational Sciences, Baylor College of Medicine, Houston, TX, USA

    Yanding Zhao & Chao Cheng

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Contributions

B.K.W. and X.W. conceived the experiments and study design. A.M. and W.H.H. designed and performed the TurboID experiments. B.W.K., A.M. and X.W. performed the CUT&RUN, ATAC-seq, RNA-seq and HiChIP experiments. L.T.D., I.S.L. and S.A.G. helped with the TurboID experiments. B.K.W. and Y.Z. performed computational analyses. N.W.S. analyzed the RNA-seq data. C.C. supervised the computational analysis. All authors contributed to the interpretation of experiments. B.K.W., A.M. and X.W. wrote the manuscript, with input from all co-authors.

Corresponding authors

Correspondence to Chao Cheng or Xiaofeng Wang.

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Competing interests

B.K.W. consults for SQZ Biotechnologies. The other authors declare no competing interests.

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Nature Structural & Molecular Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling editor: Carolina Perdigoto, in collaboration with the Nature Structural & Molecular Biology team. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Co-immunoprecipitation of SMARCC1 with indicated TurboID fusion subunits.

Co-immunoprecipitation of SMARCC1 with indicated TurboID fusion subunits and endogenous subunits showing how fusion of TurboID could impair subunit interaction with core subunit SMARCC1, indicating impaired ability to form intact complex.

Source data

Extended Data Fig. 2 SWI/SNF interactome via proximity-based labeling.

a. Glycerol sedimentation (10–35%) assay of major SWI/SNF core subunits (SMARCC1, SMARCC2, SMARCA4, SMARCD1, ACTL6A), subcomplex specific subunits (BAF: ARID1A, ARID1B, DPF2; PBAF: ARID2, PBRM1, PHF10; GBAF/ncBAF: BRD9, GLTSCR1) in G401 cells without SMARCB1 (Day 0) and SMARCB1 re-expression at Day 1, 3, and 7, showing rapid assembly of BAF and PBAF complexes and shift of subunits from GBAF to BAF and PBAF. b. Glycerol sedimentation assay of G401 SMARCD1-miniTurbo cells with and without SMARCB1, demonstrating SMARCD1-miniTurboID migrates similarly to endogenous SMARCD1. c. Western blot of Streptavidin IP of SMARCD1-TurboID and SMARCD1-miniTurboID nuclear lysate after different timepoints of exogenous biotin treatment. d. Volcano plot of TMT values for peptides labeled by SMARCD1-TurboID in G401 cells (Day 3 of SMARCB1 addback) compared to control NLS-TurboID G401 cells. e. Volcano plot of TMT values for peptides labeled by SMARCD1-TurboID in G401 cells (Day 3 of SMARCB1 addback) compared to SMARCD1-miniTurboID. T test function was used with each group’s protein expression data as input, and p values were generated by two-sided tests, no adjustment p values were used.

Source data

Extended Data Fig. 3 Dynamics of SWI/SNF subcomplexes targeting.

a. CUT&RUN peak numbers of SWI/SNF subunits: SMARCC1, ARID1A, PBRM1, and BRD9 in G401 cells without SMARCB1 (Day 0) and with SMARCB1 addback time points (Day 1, 3, and 7). b. Venn diagram comparison of CUT&RUN peak numbers of SWI/SNF subunits: SMARCC1, ARID1A, PBRM1, and BRD9 in G401 cells without SMARCB1 (Day 0) and with SMARCB1 addback time points (Day 1, 3, and 7). c. Genomic features of ARID1A regions overlapped with PBRM1, BRD9, and SMARCC1 (Top left), SMARCC1 regions overlapped with PBR1, BRD9, and ARID1A (Top right), BRD9 regions overlapped with PBRM1, ARID1A, and SMARCC1 (Bottom left), PBRM1 regions overlapped with ARID1A, BRD9, and SMARCC1 (Bottom right). d. Heatmap of HOMER identified motifs enriched in ARID1A, BRD9, PBRM1, and SMARCC1 CUT&RUN peaks over a time-course of SMARCB1 addback. T test function was used and p values were generated by two-sided tests, no adjustment p values were used. e. Heatmap of the percentage of peaks containing the motifs identified in part D for each peak set.

Source data

Extended Data Fig. 4 Dynamics of SWI/SNF subcomplexes targeting.

a. Heatmaps of GBAF specific subunit BRD9 with histone marks aligned to all BRD9 peaks in G401 cells. TSS-proximal is defined ± 2 Kb of TSS, TSS-distal is all regions outside 2 Kb of TSS. b. Heatmaps of PBAF specific subunit PBRM1 with histone marks aligned to all PBRM1 peaks in G401 cells. TSS-proximal is defined ±2 Kb of TSS, TSS-distal is all regions outside 2 Kb of TSS. c. Heatmaps of profiled SWI/SNF subunits and histone marks aligned to all SMARCC1 peaks. TSS-proximal is defined ±2 Kb of TSS, TSS-distal is all regions outside 2 Kb of TSS. d. Number of differential K27ac / K4me1 peaks over our time course (by DiffBind) at ARID1A, PBRM1, and BRD9 bound regions. The respective histone’s time point was compared against Day 0, specifically at peak regions contained by the respective SWI/SNF subunit. Differentially gained regions are defined as regions with an FDR < = 0.05, and log2FC > 0. e. Additional examples of SWI/SNF subunits targeting and histone marks using WashU Epigenome Browser, showing gained ARID1A, and/or PBRM1, and/or BRD9 binding upon SMARCB1 addback co-occurring with gained enhancer mark K27ac and K4me1.

Extended Data Fig. 5 SWI/SNF complex interacts with AP-1 complex and colocalizes on genome.

a. Western blot of G401 cells at Day 0 and 3 of SMARCB1 addback Immuno-Precipitated with AP-1 family proteins. b. Venn diagram comparison of CUT&RUN peak numbers of AP-1 subunits pJUN, JUND, and JUNB with ARID1A, PBRM1, and BRD9 without SMARCB1 (Day 0) and SMARCB1 re-expression (Day 1 and Day 3). c. Heat maps of SWI/SNF subunits ARID1A, PBRM1, BRD9, SMARCC1, and AP-1 subunits pJUN and JUNB aligned to all JUND peaks in G401 cells. TSS-proximal is defined ±2 Kb of TSS, TSS-distal is all regions outside 2 Kb of TSS. d. Heat maps of SWI/SNF subunits ARID1A, PBRM1, BRD9, SMARCC1, and AP-1 subunits pJUN and JUNB aligned to all JUNB peaks in G401 cells. TSS-proximal is defined ±2 Kb of TSS, TSS-distal is all regions outside 2 Kb of TSS. e. Average profile of SMARCC1 and ARID1A CUT&RUN signal before and after SMARCB1 addback following AP-1 depletion compared to a non-targeting control.

Extended Data Fig. 6 Cooperative targeting between SWI/SNF complex and AP-1 complex.

a. Proportion of fragments >120 bp in ARID1A, BRD9, PBRM1, and SMARCC1 CUT&RUN samples at indicated time points demonstrating the remodeling capacity of ARID1A-BAF complex (related to Fig. 5c). b. Proportion of fragments >120 bp in pJUN, JUND, and JUNB CUT&RUN samples at indicated time points (related to Fig. 5d). c. ChIPseeker genomic feature analysis of ATAC-seq peaks identified in G401 cells at each timepoint of SMARCB1 addback. d. HOMER Motif enrichment for ATAC-seq peaks identified in G401 cells at each timepoint of SMARCB1 addback. e. Specific examples using the WashU Epigenome browser showing regions that gain SWI/SNF and AP-1 binding after SMARCB1 addback, resulting in increased chromatin accessibility.

Source data

Extended Data Fig. 7 SWI/SNF complex mediated 3-D enhancer landscapes.

a. Summary of loops identified in K27ac and ARID1A HiChIP experiments. b. Additional example of SWI/SNF subunits SMARCC1, ARID1A, PBRM1, and BRD9 binding positions (CUT&RUN), and K27ac and ARID1A HiChIP using WashU Epigenome Browser, highlighting colocalization of SWI/SNF complex enrichment at enhancer anchors as well as overlapping loops between K27ac and ARID1A HiChIP (Left); Shown in the volcano plots highlighting genes in this region (CEBPB, KCNB1, PREX1, NCOA3) that are upregulated (Right). P values were generated by two-sided tests. c-j. Density heat-map showing correlation of altered K27ac loops with various factors’ CUT&RUN signal change at loop anchors: correlation of K27ac loop log fold change compared to BRD9 CUT&RUN signal log2 fold change (Day3/Day0) at corresponding anchor positions (C); correlation of K27ac loop log fold change compared to BRD9 CUT&RUN signal log2 fold change (Day3/Day0) at corresponding anchor positions that had static K27ac CUT&RUN signal across time (−1 < log2FC < 1) (D); correlation of K27ac loop log fold change compared to PBRM1 CUT&RUN signal log2 fold change (Day3/Day0) at corresponding anchor positions (E); correlation of K27ac loop log fold change compared to PBRM1 CUT&RUN signal log2 fold change (Day3/Day0) at corresponding anchor positions that had static K27ac CUT&RUN signal across time (−1 < log2FC < 1) (F); correlation of K27ac loop log fold change compared to JUNB CUT&RUN signal log2 fold change (Day3/Day0) at corresponding anchor positions (G); correlation of K27ac loop log fold change compared to JUNB CUT&RUN signal log2 fold change (Day3/Day0) at corresponding anchor positions that had static K27ac CUT&RUN signal across time (−1 < log2FC < 1) (H); correlation of K27ac loop log fold change compared to JUND CUT&RUN signal log2 fold change (Day3/Day0) at corresponding anchor positions (I); correlation of K27ac loop log fold change compared to JUND CUT&RUN signal log2 fold change (Day3/Day0) at corresponding anchor positions that had static K27ac CUT&RUN signal across time (−1 < log2FC < 1) (J). k. Differential K27ac HiChIP Enhancer-Promoter, Enhancer-Enhancer, and Promoter-Promoter loops upon AP-1 depletion.

Source data

Supplementary information

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Supplementary Table 1

Supplementary table for raw mass spectrometry data.

Source data

Source Data Fig. 1

Unprocessed western blots for Fig. 1.

Source Data Fig. 2

Statistical source data for Fig. 2a.

Source Data Fig. 3

Unprocessed western blots for Fig. 3.

Source Data Fig. 5

Statistical source data for Fig. 5b-d.

Source Data Fig. 6

Statistical source data for Fig. 6c,k.

Source Data Extended Data Fig. 1

Unprocessed western blots for Extended Data Fig. 1.

Source Data Extended Data Fig. 2

Unprocessed western blots for Extended Data Fig. 2.

Source Data Extended Data Fig. 3

Statistical source data for Extended Data Fig. 3c.

Source Data Extended Data Fig. 6

Statistical source data for Extended Data Fig. 6a-c.

Source Data Extended Data Fig. 7

Statistical source data for Extended Data Fig. 7a,k.

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Wolf, B.K., Zhao, Y., McCray, A. et al. Cooperation of chromatin remodeling SWI/SNF complex and pioneer factor AP-1 shapes 3D enhancer landscapes. Nat Struct Mol Biol 30, 10–21 (2023). https://doi.org/10.1038/s41594-022-00880-x

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