NuRD subunit CHD4 regulates super-enhancer accessibility in rhabdomyosarcoma and represents a general tumor dependency
| Autor: | Blaz Pavlovic, Javed Khan, Yeonjoo Chung, Marco Wachtel, Young K. Song, Beat W. Schäfer, Quy A. Ngo, Joana G. Marques, Matthias Gstaiger, Fabian Frommelt, Berkley E. Gryder, Dominik Laubscher, Katharina Benischke |
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| Přispěvatelé: | University of Zurich, Khan, Javed, Schäfer, Beat W |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
QH301-705.5 Science DNA accessibility Repressor 610 Medicine & health RNA polymerase II General Biochemistry Genetics and Molecular Biology Chromatin remodeling chromatin remodeling 03 medical and health sciences 0302 clinical medicine Super-enhancer 1300 General Biochemistry Genetics and Molecular Biology 2400 General Immunology and Microbiology Cell Line Tumor NuRD super-enhancer Humans Biology (General) Cancer Biology General Immunology and Microbiology biology General Neuroscience 2800 General Neuroscience Promoter General Medicine Mi-2/NuRD complex CHD4 3. Good health Cell biology Chromatin Gene Expression Regulation Neoplastic 030104 developmental biology Histone 10036 Medical Clinic 030220 oncology & carcinogenesis biology.protein Medicine rhabdomyosarcoma Mi-2 Nucleosome Remodeling and Deacetylase Complex Research Article Human |
| Zdroj: | eLife, Vol 9 (2020) eLife eLife, 9 |
| ISSN: | 2050-084X |
| DOI: | 10.3929/ethz-b-000438609 |
| Popis: | The NuRD complex subunit CHD4 is essential for fusion-positive rhabdomyosarcoma (FP-RMS) survival, but the mechanisms underlying this dependency are not understood. Here, a NuRD-specific CRISPR screen demonstrates that FP-RMS is particularly sensitive to CHD4 amongst the NuRD members. Mechanistically, NuRD complex containing CHD4 localizes to super-enhancers where CHD4 generates a chromatin architecture permissive for the binding of the tumor driver and fusion protein PAX3-FOXO1, allowing downstream transcription of its oncogenic program. Moreover, CHD4 depletion removes HDAC2 from the chromatin, leading to an increase and spread of histone acetylation, and prevents the positioning of RNA Polymerase 2 at promoters impeding transcription initiation. Strikingly, analysis of genome-wide cancer dependency databases identifies CHD4 as a general cancer vulnerability. Our findings describe CHD4, a classically defined repressor, as positive regulator of transcription and super-enhancer accessibility as well as establish this remodeler as an unexpected broad tumor susceptibility and promising drug target for cancer therapy. eLife, 9 ISSN:2050-084X |
| Databáze: | OpenAIRE |
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