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Multiple interactions of the oncoprotein transcription factor MYC with the SWI/SNF chromatin remodeler

Oncogene volume 40, pages 3593–3609 (2021)Cite this article

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Abstract

The SNF5 subunit of the SWI/SNF chromatin remodeling complex has been shown to act as a tumor suppressor through multiple mechanisms, including impairing the ability of the oncoprotein transcription factor MYC to bind chromatin. Beyond SNF5, however, it is unknown to what extent MYC can access additional SWI/SNF subunits or how these interactions affect the ability of MYC to drive transcription, particularly in SNF5-null cancers. Here, we report that MYC interacts with multiple SWI/SNF components independent of SNF5. We show that MYC binds the pan-SWI/SNF subunit BAF155 through the BAF155 SWIRM domain, an interaction that is inhibited by the presence of SNF5. In SNF5-null cells, MYC binds with remaining SWI/SNF components to essential genes, although for a purpose that is distinct from chromatin remodeling. Analysis of MYC–SWI/SNF target genes in SNF5-null cells reveals that they are associated with core biological functions of MYC linked to protein synthesis. These data reveal that MYC can bind SWI/SNF in an SNF5-independent manner and that SNF5 modulates access of MYC to core SWI/SNF complexes. This work provides a framework in which to interrogate the influence of SWI/SNF on MYC function in cancers in which SWI/SNF or MYC are altered.

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Fig. 1: MYC does not require SNF5 to interact with SWI/SNF subunits.
Fig. 2: MYC co-localizes with SWI/SNF subunits on chromatin in malignant rhabdoid tumor cell lines.
Fig. 3: BAF155 is universally localized at MYC-SWI/SNF co-bound sites in other SWI/SNF altered cancers.
Fig. 4: MYC can access SWI/SNF through interactions with the SWIRM domain of BAF155.
Fig. 5: Engineering G401 cells to track acute changes to MYC target genes.
Fig. 6: MYC loss results in widespread gene expression changes.
Fig. 7: Impact of MYC loss on MYC-SWI/SNF target gene expression.

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Data availability

All sequencing data have been deposited at GEO with the accession number GSE164926. All next-generation sequencing data metrics are shown in Supplementary Table 6. Any other data are available upon request.

References

  1. Tansey WP. Mammalian MYC proteins and cancer. N. J Sci. 2014;2013:1–27.

    Google Scholar 

  2. Thomas LR, Tansey WP. MYC and chromatin. Open Access J Sci Technol. 2015;3:101124.

    Article  Google Scholar 

  3. Hohmann AF, Vakoc CR. A rationale to target the SWI/SNF complex for cancer therapy. Trends Genet. 2014;30:356–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Reddy D, Workman JL. Targeting BAF-perturbed cancers. Nat Cell Biol. 2018;20:1332–3.

    Article  CAS  PubMed  Google Scholar 

  5. Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 2013;45:592–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shain AH, Pollack JR. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS ONE. 2013;8:e55119.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Nakayama RT, Pulice JL, Valencia AM, McBride MJ, McKenzie ZM, Gillespie MA, et al. SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat Genet. 2017;49:1613–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang X, Lee RS, Alver BH, Haswell JR, Wang S, Mieczkowski J, et al. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat Genet. 2017;49:289–95.

    Article  CAS  PubMed  Google Scholar 

  9. Gatchalian J, Malik S, Ho J, Lee DS, Kelso TWR, Shokhirev MN, et al. A non-canonical BRD9-containing BAF chromatin remodeling complex regulates naive pluripotency in mouse embryonic stem cells. Nat Commun. 2018;9:5139.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Michel BC, D’Avino AR, Cassel SH, Mashtalir N, McKenzie ZM, McBride MJ, et al. A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat Cell Biol. 2018;20:1410–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang X, Wang S, Troisi EC, Howard TP, Haswell JR, Wolf BK, et al. BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors. Nat Commun. 2019;10:1881.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mittal P, Roberts CWM. The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol. 2020;17:435–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alver BH, Kim KH, Lu P, Wang X, Manchester HE, Wang W, et al. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers. Nat Commun. 2017;8:14648.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Alpsoy A, Dykhuizen EC. Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes. J Biol Chem. 2018;293:3892–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cheng SW, Davies KP, Yung E, Beltran RJ, Yu J, Kalpana GV. c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function. Nat Genet. 1999;22:102–5.

    Article  CAS  PubMed  Google Scholar 

  16. Stojanova A, Tu WB, Ponzielli R, Kotlyar M, Chan PK, Boutros PC, et al. MYC interaction with the tumor suppressive SWI/SNF complex member INI1 regulates transcription and cellular transformation. Cell Cycle. 2016;15:1693–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Weissmiller AM, Wang J, Lorey SL, Howard GC, Martinez E, Liu Q, et al. Inhibition of MYC by the SMARCB1 tumor suppressor. Nat Commun. 2019;10:2014.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gadd S, Sredni ST, Huang CC, Perlman EJ, Renal Tumor Committee of the Children’s Oncology Group. Rhabdoid tumor: gene expression clues to pathogenesis and potential therapeutic targets. Lab Invest. 2010;90:724–38.

  19. Wang X, Werneck MB, Wilson BG, Kim HJ, Kluk MJ, Thom CS, et al. TCR-dependent transformation of mature memory phenotype T cells in mice. J Clin Investig. 2011;121:3834–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Genovese G, Carugo A, Tepper J, Robinson FS, Li L, Svelto M, et al. Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer. Nature 2017;542:362–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Thomas LR, Wang Q, Grieb BC, Phan J, Foshage AM, Sun Q, et al. Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. Mol Cell. 2015;58:440–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Thomas LR, Foshage AM, Weissmiller AM, Popay TM, Grieb BC, Qualls SJ, et al. Interaction of MYC with host cell factor-1 is mediated by the evolutionarily conserved Myc box IV motif. Oncogene 2016;35:3613–8.

    Article  CAS  PubMed  Google Scholar 

  23. Ji H, Wu G, Zhan X, Nolan A, Koh C, De Marzo A, et al. Cell-type independent MYC target genes reveal a primordial signature involved in biomass accumulation. PLoS ONE. 2011;6:e26057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. McBride MJ, Pulice JL, Beird HC, Ingram DR, D’Avino AR, Shern JF, et al. The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma. Cancer Cell. 2018;33:1128–41.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pan J, McKenzie ZM, D’Avino AR, Mashtalir N, Lareau CA, St Pierre R, et al. The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity-independent genomic targeting. Nat Genet. 2019;51:618–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Orlando KA, Douglas AK, Abudu A, Wang Y, Tessier-Cloutier B, Su W, et al. Re-expression of SMARCA4/BRG1 in small cell carcinoma of ovary, hypercalcemic type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism. eLife. 2020;9:e59073.

  27. Boyer LA, Langer MR, Crowley KA, Tan S, Denu JM, Peterson CL. Essential role for the SANT domain in the functioning of multiple chromatin remodeling enzymes. Mol Cell. 2002;10:935–42.

    Article  CAS  PubMed  Google Scholar 

  28. Boyer LA, Latek RR, Peterson CL. The SANT domain: a unique histone-tail-binding module? Nat Rev Mol Cell Biol. 2004;5:158–63.

    Article  CAS  PubMed  Google Scholar 

  29. Sohn DH, Lee KY, Lee C, Oh J, Chung H, Jeon SH, et al. SRG3 interacts directly with the major components of the SWI/SNF chromatin remodeling complex and protects them from proteasomal degradation. J Biol Chem. 2007;282:10614–24.

    Article  CAS  PubMed  Google Scholar 

  30. Wang L, Zhao Z, Meyer MB, Saha S, Yu M, Guo A, et al. CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer cell. 2014;25:21–36.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Mashtalir N, D’Avino AR, Michel BC, Luo J, Pan J, Otto JE, et al. Modular organization and assembly of SWI/SNF family chromatin remodeling complexes. Cell 2018;175:1272–88. e20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang W, Xue Y, Zhou S, Kuo A, Cairns BR, Crabtree GR. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev. 1996;10:2117–30.

    Article  CAS  PubMed  Google Scholar 

  33. Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods. 2013;10:1213–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vierbuchen T, Ling E, Cowley CJ, Couch CH, Wang X, Harmin DA, et al. AP-1 transcription factors and the BAF complex mediate signal-dependent enhancer selection. Mol Cell. 2017;68:1067–82.e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8:2281–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Campeau E, Ruhl VE, Rodier F, Smith CL, Rahmberg BL, Fuss JO, et al. A versatile viral system for expression and depletion of proteins in mammalian cells. PLoS One. 2009;4:e6529.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Nabet B, Roberts JM, Buckley DL, Paulk J, Dastjerdi S, Yang A, et al. The dTAG system for immediate and target-specific protein degradation. Nat Chem Biol. 2018;14:431–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Phelan ML, Sif S, Narlikar GJ, Kingston RE. Reconstitution of a core chromatin remodeling complex from SWI/SNF subunits. Mol Cell. 1999;3:247–53.

    Article  CAS  PubMed  Google Scholar 

  39. Wilson AC, Peterson MG, Herr W. The HCF repeat is an unusual proteolytic cleavage signal. Genes Dev. 1995;9:2445–58.

    Article  CAS  PubMed  Google Scholar 

  40. Langmead B, Trapnell C, Pop M, Salzberg SL. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009;10:R25.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Feng J, Liu T, Qin B, Zhang Y, Liu XS. Identifying ChIP-seq enrichment using MACS. Nat Protoc. 2012;7:1728–40.

    Article  CAS  PubMed  Google Scholar 

  42. Stark RB, G.D. DiffBind: differential binding analysis of ChIP-seq peak data. Bioconductor. 2011. https://doi.org/10.1038/s41388-021-01804-7

  43. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 2011;17:10–2.

    Article  Google Scholar 

  45. Wang J, Zhao Y, Zhou X, Hiebert SW, Liu Q, Shyr Y. Nascent RNA sequencing analysis provides insights into enhancer-mediated gene regulation. BMC Genomics. 2018;19:633.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 2013;29:15–21.

    Article  CAS  PubMed  Google Scholar 

  47. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 2014;30:923–30.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Special thanks to Dr. Scott Hiebert for his invaluable contributions. We would also like to thank the Vanderbilt University Medical Center Flow Cytometry Shared Resource, the Vanderbilt University Chemical Synthesis Core, the Vanderbilt Cell Imaging Shared Resource (CISR), and the Vanderbilt University Medical Center Technologies for Advanced Genomics (VANTAGE) Core for their critical assistance in this project. The Nikon Center of Excellence located in CISR is supported by NIH grants CA68485, DK20593, DK58404, DK59637, and EY08126. This work was supported by The Rally Foundation for Childhood Cancer Research Young Investigator Award and T32CA119925 to A.M.W, by the NIH/NCI, F31CA225065 and T32CA009582 to A.D.G, and grants from Alex’s Lemonade Stand Foundation, St. Baldrick’s Foundation, the Robert J. Kleberg and Helen C. Kleberg Foundation, and grant CA247833 from the NIH/NCI to W.P.T.

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  1. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Chase M. Woodley, Alissa D. Guarnaccia, David L. Elion, Kiana Guerrazzi, Tyler S. McCann, Tessa M. Popay, Shelly L. Lorey & William P. Tansey

  2. Department of Biology, Middle Tennessee State University, Murfreesboro, TN, USA

    Alexander S. Romer, Jack N. Maxwell & April M. Weissmiller

  3. Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA

    Jing Wang & Qi Liu

  4. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

    Jing Wang & Qi Liu

  5. Vanderbilt University Medical Center Flow Cytometry Shared Resource, Vanderbilt University Medical Center, Nashville, TN, USA

    Brittany K. Matlock & David K. Flaherty

  6. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA

    William P. Tansey

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Woodley, C.M., Romer, A.S., Wang, J. et al. Multiple interactions of the oncoprotein transcription factor MYC with the SWI/SNF chromatin remodeler. Oncogene 40, 3593–3609 (2021). https://doi.org/10.1038/s41388-021-01804-7

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