Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human cancers.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
01
06
2018
accepted:
04
06
2019
pubmed:
21
8
2019
medline:
24
1
2020
entrez:
21
8
2019
Statut:
ppublish
Résumé
Aberrations in genes coding for subunits of the BRG1/BRM associated factor (BAF) chromatin remodeling complexes are highly abundant in human cancers. Currently, it is not understood how these mostly loss-of-function mutations contribute to cancer development and how they can be targeted therapeutically. The cancer-type-specific occurrence patterns of certain subunit mutations suggest subunit-specific effects on BAF complex function, possibly by the formation of aberrant residual complexes. Here, we systematically characterize the effects of individual subunit loss on complex composition, chromatin accessibility and gene expression in a panel of knockout cell lines deficient for 22 BAF subunits. We observe strong, specific and sometimes discordant alterations dependent on the targeted subunit and show that these explain intracomplex codependencies, including the synthetic lethal interactions SMARCA4-ARID2, SMARCA4-ACTB and SMARCC1-SMARCC2. These data provide insights into the role of different BAF subcomplexes in genome-wide chromatin organization and suggest approaches to therapeutically target BAF-mutant cancers.
Identifiants
pubmed: 31427792
doi: 10.1038/s41588-019-0477-9
pii: 10.1038/s41588-019-0477-9
pmc: PMC6952272
mid: EMS83287
doi:
Substances chimiques
ARID2 protein, human
0
DNA-Binding Proteins
0
Nuclear Proteins
0
SMARCC1 protein, human
0
SMARCC2 protein, human
0
Transcription Factors
0
SMARCA4 protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1399-1410Subventions
Organisme : European Research Council
ID : 772437
Pays : International
Références
Wang, W. et al. Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J. 15, 5370–5382 (1996).
doi: 10.1002/j.1460-2075.1996.tb00921.x
Kadoch, C. & Crabtree, G. R. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci. Adv. 1, e1500447 (2015).
doi: 10.1126/sciadv.1500447
Phelan, M. L., Sif, S., Narlikar, G. J. & Kingston, R. E. Reconstitution of a core chromatin remodeling complex from SWI/SNF subunits. Mol. Cell 3, 247–253 (1999).
doi: 10.1016/S1097-2765(00)80315-9
Chandler, R. L. et al. ARID1a-DNA interactions are required for promoter occupancy by SWI/SNF. Mol. Cell Biol. 33, 265–280 (2013).
doi: 10.1128/MCB.01008-12
Hodges, C., Kirkland, J. G. & Crabtree, G. R. The many roles of BAF (mSWI/SNF) and PBAF complexes in cancer. Cold Spring Harb. Perspect. Med. 6, a026930 (2016).
doi: 10.1101/cshperspect.a026930
Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45, 592–601 (2013).
doi: 10.1038/ng.2628
Hoffman, G. R. et al. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc. Natl Acad. Sci. USA 111, 3128–3133 (2014).
doi: 10.1073/pnas.1316793111
Wilson, B. G. et al. Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol. Cell. Biol. 34, 1136–1144 (2014).
doi: 10.1128/MCB.01372-13
Oike, T. et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res. 73, 5508–5518 (2013).
doi: 10.1158/0008-5472.CAN-12-4593
Helming, K. C. et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat. Med. 20, 251–254 (2014).
doi: 10.1038/nm.3480
Kelso, T. W R. et al. Chromatin accessibility underlies synthetic lethality of SWI/SNFsubunits in ARID1A-mutant cancers. eLife 6, e30506 (2017).
doi: 10.7554/eLife.30506
Mathur, R. et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat. Genet. 49, 296–302 (2017).
doi: 10.1038/ng.3744
Mashtalir, N. et al. Modular organization and assembly of SWI/SNF family chromatin remodeling complexes. Cell 175, 1272–1288.e20 (2018).
doi: 10.1016/j.cell.2018.09.032
Alpsoy, A. & Dykhuizen, E. C. Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes. J. Biol. Chem. 293, 3892–3903 (2018).
doi: 10.1074/jbc.RA117.001065
Dutta, A. et al. Composition and function of mutant Swi/Snf Complexes. Cell Rep. 18, 2124–2134 (2017).
doi: 10.1016/j.celrep.2017.01.058
Sen, P. et al. Loss of Snf5 induces formation of an aberrant SWI/SNF complex. Cell Rep. 18, 2135–2147 (2017).
doi: 10.1016/j.celrep.2017.02.017
Blomen, V. A. et al. Gene essentiality and synthetic lethality in haploid human cells. Science 350, 1092–1096 (2015).
doi: 10.1126/science.aac7557
Yan, Z. et al. PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes. Genes Dev. 19, 1662–1667 (2005).
doi: 10.1101/gad.1323805
Michel, B. C. et al. A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat. Cell Biol. 20, 1410–1420 (2018).
doi: 10.1038/s41556-018-0221-1
Pan, J. et al. Interrogation of mammalian protein complex structure, function, and membership using genome-scale fitness screens. Cell Syst. 6, 555–568.e7 (2018).
doi: 10.1016/j.cels.2018.04.011
Wang, X. F. et al. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat. Genet. 49, 289–295 (2017).
doi: 10.1038/ng.3746
Hodges, H. C. et al. Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers. Nat. Struct. Mol. Biol. 25, 61–72 (2018).
doi: 10.1038/s41594-017-0007-3
Raab, J. R., Resnick, S. & Magnuson, T. Genome-wide transcriptional regulation mediated by biochemically distinct SWI/SNF complexes. PLoS Genet. 11, e1005748 (2015).
doi: 10.1371/journal.pgen.1005748
Valianou, M. et al. Pharmacological inhibition of Polo-like kinase 1 (PLK1) by BI-2536 decreases the viability and survival of hamartin and tuberin deficient cells via induction of apoptosis and attenuation of autophagy. Cell Cycle 14, 399–407 (2015).
doi: 10.4161/15384101.2014.986394
Wang, N. N. et al. Molecular targeting of the oncoprotein PLK1 in pediatric acute myeloid leukemia: RO3280, a novel PLK1 inhibitor, induces apoptosis in leukemia cells. Int. J. Mol. Sci. 16, 1266–1292 (2015).
doi: 10.3390/ijms16011266
Zhao, C. L. et al. Downregulation of PLK1 by RNAi attenuates the tumorigenicity of esophageal squamous cell carcinoma cells via promoting apoptosis and inhibiting angiogenesis. Neoplasma 62, 748–755 (2015).
doi: 10.4149/neo_2015_089
Wang, W. et al. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev. 10, 2117–2130 (1996).
doi: 10.1101/gad.10.17.2117
Zhao, K. et al. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95, 625–636 (1998).
doi: 10.1016/S0092-8674(00)81633-5
Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).
doi: 10.1038/nature11003
McFarland, J. M. et al. Improved estimation of cancer dependencies from large-scale RNAi screens using model-based normalization and data integration. Nat. Commun. 9, 4610 (2018).
doi: 10.1038/s41467-018-06916-5
Stransky, N. et al. Pharmacogenomic agreement between two cancer cell line data sets. Nature 528, 84–87 (2015).
doi: 10.1038/nature15736
Meyers, R. M. et al. Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells. Nat. Genet. 49, 1779–1784 (2017).
doi: 10.1038/ng.3984
McDonald, E. R.3rd et al. Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening. Cell 170, 577–592.e10 (2017).
doi: 10.1016/j.cell.2017.07.005
Tsherniak, A. et al. Defining a cancer dependency map. Cell 170, 564–576.e16 (2017).
doi: 10.1016/j.cell.2017.06.010
Buenrostro, J. D., Wu, B., Chang, H. Y. & Greenleaf, W. J. ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr. Protoc. Mol. Biol. 109, 1–9 (2015).
Schmidl, C., Rendeiro, A. F., Sheffield, N. C. & Bock, C. ChIPmentation: fast, robust, low-input ChIP-seq for histones and transcription factors. Nat. Methods 12, 963–965 (2015).
doi: 10.1038/nmeth.3542
Jiang, H., Lei, R., Ding, S. W. & Zhu, S. Skewer: a fast and accurate adapter trimmer for next-generation sequencing paired-end reads. BMC Bioinformatics 15, 182 (2014).
doi: 10.1186/1471-2105-15-182
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).
doi: 10.1038/nmeth.1923
Tarasov, A., Vilella, A. J., Cuppen, E., Nijman, I. J. & Prins, P. Sambamba: fast processing of NGS alignment formats. Bioinformatics 31, 2032–2034 (2015).
doi: 10.1093/bioinformatics/btv098
Quinlan, A. R. BEDTools: the Swiss-army tool for genome feature analysis. Curr. Protoc. Bioinformatics 47, 1–34 (2014).
doi: 10.1002/0471250953.bi1112s47
Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).
doi: 10.1186/gb-2008-9-9-r137
Hoffman, M. M. et al. Integrative annotation of chromatin elements from ENCODE data. Nucleic Acids Res. 41, 827–841 (2013).
doi: 10.1093/nar/gks1284
Landt, S. G. et al. ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia. Genome Res. 22, 1813–1831 (2012).
doi: 10.1101/gr.136184.111
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).
doi: 10.1016/j.molcel.2010.05.004
Ernst, J. & Kellis, M. Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat. Biotechnol. 28, 817–825 (2010).
doi: 10.1038/nbt.1662
Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014).
doi: 10.1093/bioinformatics/btu170
Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).
doi: 10.1186/gb-2009-10-3-r25
Glaus, P., Honkela, A. & Rattray, M. Identifying differentially expressed transcripts from RNA-seq data with biological variation. Bioinformatics 28, 1721–1728 (2012).
doi: 10.1093/bioinformatics/bts260
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
doi: 10.1186/s13059-014-0550-8
Pedregosa, F. et al. Scikit-learn: machine learning in Python. J. Mach. Learn. Res. 12, 2825–2830 (2011).
Sheffield, N. C. & Bock, C. LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor. Bioinformatics 32, 587–589 (2016).
doi: 10.1093/bioinformatics/btv612
Sheffield, N. C. et al. Patterns of regulatory activity across diverse human cell types predict tissue identity, transcription factor binding, and long-range interactions. Genome Res. 23, 777–788 (2013).
doi: 10.1101/gr.152140.112
Sánchez-Castillo, M. et al. CODEX: a next-generation sequencing experiment database for the haematopoietic and embryonic stem cell communities. Nucleic Acids Res. 43, D1117–D1123 (2015).
doi: 10.1093/nar/gku895
Rosenbloom, K. R. et al. The UCSC Genome Browser database: 2015 update. Nucleic Acids Res. 43, D670–D681 (2015).
doi: 10.1093/nar/gku1177
Liu, T. et al. Cistrome: an integrative platform for transcriptional regulation studies. Genome Biol. 12, R83 (2011).
doi: 10.1186/gb-2011-12-8-r83
Adams, D. et al. BLUEPRINT to decode the epigenetic signature written in blood. Nat. Biotechnol. 30, 224–226 (2012).
doi: 10.1038/nbt.2153
Bailey, T. L. et al. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 37, W202–W208 (2009).
doi: 10.1093/nar/gkp335
Schep, A. N. et al. Structured nucleosome fingerprints enable high-resolution mapping of chromatin architecture within regulatory regions. Genome Res. 25, 1757–1770 (2015).
doi: 10.1101/gr.192294.115