Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human cancers

Abstract

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.

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Fig. 1: An isogenic cell line panel for loss of individual BAF subunits.
Fig. 2: BAF complex composition changes following knockout of single BAF-coding genes.
Fig. 3: Knockout of single BAF-coding genes alters global chromatin accessibility.
Fig. 4: Expression changes correlate with altered chromatin accessibility.
Fig. 5: Systematic targeting of multiple BAF subunits identifies previously unknown intracomplex synthetic lethalities.
Fig. 6: Integrative view of BAF complex subunit dependencies and functional similarity.

Data availability

Next-generation sequencing data have been deposited with the NCBI GEO (GSE108390). Mass spectrometry data have been deposited with the PRIDE archive PXD013102. The processed data used for the analyses are available at http://baf-complex.computational-epigenetics.org.

Code availability

Software used for the analyses is available at http://baf-complex.computational-epigenetics.org.

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Acknowledgements

We thank the Biomedical Sequencing Facility, the Proteomics and Metabolomics Facility and the Platform Austria for Chemical Biology at CeMM for their support in generating and analyzing the next-generation sequencing, proteomics or screening data, respectively. We gratefully acknowledge Horizon Discovery for providing the HAP1 cell lines, and Boehringer Ingelheim, the Superti-Furga laboratory (CeMM) and Winter laboratory (CeMM) for providing various cancer cell lines. We acknowledge the experimental support provided by J. Block and D. Donertas. Research in the Kubicek laboratory is supported by the Austrian Federal Ministry for Digital and Economic Affairs and the National Foundation for Research, Technology and Development, the Austrian Science Fund (FWF) F4701 and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-CoG-772437). C.B. is supported by a New Frontiers Group award of the Austrian Academy of Sciences and by an ERC Starting Grant (European Union’s Horizon 2020 research and innovation programme, grant no. 679146).

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S.S., G.B., M.P. and S.K. planned the study and designed the experiments. S.S., K.R., M.H., T.P., K.P., C.S., A.R. and B.B. performed the experiments. A.F.R., P.M., L.V., S.S. and S.K. analyzed the data. S.S. and S.K. wrote the manuscript. S.K., M.P., G.B., A.C.M., C.B. and J.M. supervised the work. S.K. provided the funding.

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Correspondence to Stefan Kubicek.

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G.B. and M.P. are employees of Boehringer Ingelheim RCV GmbH & Co KG.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–15 and Supplementary Note

Reporting Summary

Supplementary Table 1

Materials.

Supplementary Table 2

ATAC-seq.

Supplementary Table 3

ChIP-seq.

Supplementary Table 4

RNA-seq.

Supplementary Table 5

Synthetic lethality.

Supplementary Table 6

Statistics.

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Schick, S., Rendeiro, A.F., Runggatscher, K. et al. Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human cancers. Nat Genet 51, 1399–1410 (2019). https://doi.org/10.1038/s41588-019-0477-9

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