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      SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation

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          Abstract

          SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex 1, 2 , is inactivated in nearly all pediatric rhabdoid tumors 35 . These aggressive cancers are among the most genomically stable 68 , suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here, we show that despite indistinguishable mutational landscapes, human rhabdoid tumors show distinct enhancer H3K27ac signatures, which reveal remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting – markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared across all subtypes, such as SPRY1, and other lineage-specific super-enhancers, like SOX2 in brain-derived rhabdoid tumors. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1.

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          Most cited references21

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          Design and analysis of ChIP-seq experiments for DNA-binding proteins

          Recent progress in massively parallel sequencing platforms has allowed for genome-wide measurements of DNA-associated proteins using a combination of chromatin immunoprecipitation and sequencing (ChIP-seq). While a variety of methods exist for analysis of the established microarray alternative (ChIP-chip), few approaches have been described for processing ChIP-seq data. To fill this gap, we propose an analysis pipeline specifically designed to detect protein binding positions with high accuracy. Using three separate datasets, we illustrate new methods for improving tag alignment and correcting for background signals. We also compare sensitivity and spatial precision of several novel and previously described binding detection algorithms. Finally, we analyze the relationship between the depth of sequencing and characteristics of the detected binding positions, and provide a method for estimating the sequencing depth necessary for a desired coverage of protein binding sites.
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            Charting histone modifications and the functional organization of mammalian genomes.

            A succession of technological advances over the past decade have enabled researchers to chart maps of histone modifications and related chromatin structures with increasing accuracy, comprehensiveness and throughput. The resulting data sets highlight the interplay between chromatin and genome function, dynamic variations in chromatin structure across cellular conditions, and emerging roles for large-scale domains and higher-ordered chromatin organization. Here we review a selection of recent studies that have probed histone modifications and successive layers of chromatin structure in mammalian genomes, the patterns that have been identified and future directions for research.
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              Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes.

              Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                22 November 2016
                12 December 2016
                February 2017
                12 June 2017
                : 49
                : 2
                : 289-295
                Affiliations
                [1 ]Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
                [2 ]Division of Hematology/Oncology, Boston Children’s Hospital, MA 02215, USA
                [3 ]Department of Pediatrics, Harvard Medical School, Boston MA 02215, USA
                [4 ]Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
                [5 ]Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
                [6 ]Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
                [7 ]Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
                [8 ]Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02215, USA
                [9 ]Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles and Keck School of Medicine at University of Southern California, Los Angeles, CA 90033, USA
                [10 ]Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
                [11 ]Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
                [12 ]Comprehensive Cancer Center and Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
                Author notes
                [*]

                Co-first author

                [#]

                Co-senior author

                Article
                NIHMS831183
                10.1038/ng.3746
                5285474
                27941797
                995cfa14-4d51-4b6a-9934-54c79bcfea9c

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                Genetics
                Genetics

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