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      A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation


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          Mammalian SWI/SNF chromatin remodeling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF, and a newly-characterized non-canonical complex, ncBAF. However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma (SS) and malignant rhabdoid tumor (MRT), which share in common cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the BRD9 subunit of ncBAF rapidly attenuates SS and MRT cell proliferation. Notably, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites, and function in a manner distinct from fusion oncoprotein-bound complexes. Taken together, these findings unmask the unique chromatin targeting and function of ncBAF complexes and present new cancer-specific therapeutic targets.

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          The biology of chromatin remodeling complexes.

          The packaging of chromosomal DNA by nucleosomes condenses and organizes the genome, but occludes many regulatory DNA elements. However, this constraint also allows nucleosomes and other chromatin components to actively participate in the regulation of transcription, chromosome segregation, DNA replication, and DNA repair. To enable dynamic access to packaged DNA and to tailor nucleosome composition in chromosomal regions, cells have evolved a set of specialized chromatin remodeling complexes (remodelers). Remodelers use the energy of ATP hydrolysis to move, destabilize, eject, or restructure nucleosomes. Here, we address many aspects of remodeler biology: their targeting, mechanism, regulation, shared and unique properties, and specialization for particular biological processes. We also address roles for remodelers in development, cancer, and human syndromes.
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            The protein CTCF is required for the enhancer blocking activity of vertebrate insulators.

            An insulator is a DNA sequence that can act as a barrier to the influences of neighboring cis-acting elements, preventing gene activation, for example, when located between an enhancer and a promoter. We have identified a 42 bp fragment of the chicken beta-globin insulator that is both necessary and sufficient for enhancer blocking activity in human cells. We show that this sequence is the binding site for CTCF, a previously identified eleven-zinc finger DNA-binding protein that is highly conserved in vertebrates. CTCF sites are present in all of the vertebrate enhancer-blocking elements we have examined. We suggest that directional enhancer blocking by CTCF is a conserved component of gene regulation in vertebrates.
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              Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening

              Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.

                Author and article information

                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                4 October 2018
                05 November 2018
                December 2018
                18 August 2019
                : 20
                : 12
                : 1410-1420
                [1 ]Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA.
                [2 ]Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
                [3 ]Biomedical and Biological Sciences Program, Harvard Medical School, Boston, MA, 02115, USA.
                [4 ]Medical Scientist Training Program, Harvard Medical School, Boston, MA 02115, USA.
                [5 ]Chemical Biology Program, Harvard Medical School, Boston, MA, 02115, USA.
                [6 ]Foghorn Therapeutics, Inc., Cambridge, MA 02142.
                [7 ]Department of Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
                [8 ]Novartis Institutes for Biomedical Research, Cambridge, MA, 02139, USA.
                Author notes

                These authors each contributed significantly to this work.

                Author contributions

                B.C.M., S.H.C., A.R.D. and C.K. conceived of and designed the study. B.C.M. designed and performed most experiments, A.R.D. performed all bioinformatic analyses and statistical calculations in the manuscript. S.H.C. designed and performed GLTSCR1/1L biochemistry and contributed to ChIP-seq interpretation/analysis, Z.M.M. performed GLTSCR1/1L biochemistry, N.M. and J.P. were involved in design and execution of experiments pertaining to ncBAF biochemistry, M.J.M, and A.M.V. were involved in the design and execution of SS and MRT experiments, and J.P. contributed to analysis and interpretation of large-scale dependency data. D.I.R. synthesized dBRD9 and aided in experimental design using dBRD9, and H.J.Z., and N.F. aided in conducting GLTSCR1/1L biochemistry. H.M.C., Q.Z., and M.B. directed the CRISPR tiling experiments and L.M.M.S. performed bioinformatic analysis of these datasets. C.A.L contributed important insights and aided in data analysis and interpretation. N.S.G. and J.E.B. supervised the development of dBRD9 and helped optimize dBRD9 studies across cell lines. H.M.C and L.M.M.S contributed to the figures of the manuscript. B.C.M., A.R.D., S.H.C., and C.K. wrote the manuscript.

                []Correspondence to: Cigall Kadoch, Ph.D., Assistant Professor, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Institute Member and Epigenomics Program Co-Director, Broad Institute, 450 Brookline Avenue, D620, Boston, MA 02215, (617)-632-3789, cigall_kadoch@ 123456dfci.harvard.edu

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                Cell biology
                Cell biology


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