1. Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology
- Author
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Stefan Frank, Yulia Kargapolova, Joanna Brühl, Karim Bouazoune, Rizwan Rehimi, Jonathan Trautwein, Argyris Papantonis, Bernd Wollnik, Alvaro Rada-Iglesias, Bregje W.M. van Bon, Nicole Russ, Magdalena Laugsch, Erwan Watrin, Eduardo G. Gusmao, Hülya Kayserili, Leo Kurian, Christian Gilissen, Konstantinos Sofiadis, Anne Zirkel, Frank J. Kaiser, Han G. Brunner, Gökhan Yigit, Natasa Josipovic, Alexander Hoischen, Peter Nürnberg, Janine Altmüller, Yun Li, Athanasia Mizi, Spiros Palikyras, Gernot Längst, University of Cologne, University Hospital of Cologne [Cologne], Koç University, Philipps Universität Marburg = Philipps University of Marburg, University Medical Center Göttingen (UMG), Radboud University Medical Center [Nijmegen], University of Heidelberg, Medical Faculty, University of Regensburg, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Universidad de Cantabria [Santander], Georg-August-University = Georg-August-Universität Göttingen, Deutsche Forschungsgemeinschaft, DFG: 109546710, 2015_A125, 360043781, 397484323, CCRC2407, TRR259, Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und Molekulare Biowissenschaften, GGNB, Uniklinikum Giessen und Marburg, UKGM: 5/2016, Open Access funding enabled and organized by Projekt DEAL., Philipps University of Marburg, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Göttingen - Georg-August-Universität Göttingen, German Research Foundation, International Max Planck Research Schools, Projekt DEAL, Karabey Kayserili, Hülya (ORCID 0000-0003-0376-499X & YÖK ID 7945), Kargapolova, Yulia, Rehimi, Rizwan, Bruehl, Joanna, Sofiadis, Konstantinos, Zirkel, Anne, Palikyras, Spiros, Mizi, Athanasia, Li, Yun, Yigit, Gokhan, Hoischen, Alexander, Frank, Stefan, Russ, Nicole, Trautwein, Jonathan, van Bon, Bregje, Gilissen, Christian, Laugsch, Magdalena, Gusmao, Eduardo Gade, Josipovic, Natasa, Altmueller, Janine, Nuernberg, Peter, Laengst, Gernot, Kaiser, Frank J., Watrin, Erwan, Brunner, Han, Rada-Iglesias, Alvaro, Kurian, Leo, Wollnik, Bernd, Bouazoune, Karim, Papantonis, Argyris, and School of Medicine
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0301 basic medicine ,Epigenomics ,[SDV]Life Sciences [q-bio] ,Hallermann Streiff syndrome ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Medizin ,General Physics and Astronomy ,Gene Expression ,nerve protein ,medicine.disease_cause ,CHD6 protein ,0302 clinical medicine ,Missense mutation ,genetics ,Science and technology ,Gene Editing ,Mutation ,Multidisciplinary ,integumentary system ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Genomics ,Chromatin ,3. Good health ,Cell biology ,enzyme activity ,DNA-Binding Proteins ,Technology Platforms ,autophagy ,Protein family ,DNA damage ,phenotype ,Science ,Protein structure ,Binding domain ,Mutations ,Gene ,Stress ,PBAF ,Translocation ,Phenotypes ,SMARCB1 ,DNA helicase ,Nerve Tissue Proteins ,Biology ,chromatin assembly and disassembly ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,medicine ,Autophagy ,genomics ,Humans ,human ,Hallermann's Syndrome ,chemical binding ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,epigenetics ,DNA Helicases ,General Chemistry ,DNA ,DNA binding protein ,030104 developmental biology ,physiology ,pathology ,protein ,metabolism ,030217 neurology & neurosurgery - Abstract
© The Author(s) 2021., Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance., This work was supported by UKGM (Project 5/2016), by the Deutsche Forschungsgemeinschaft via TRR81 (Project 109546710) and CCRC2407 (Project 360043781), as well as by an Else-Kroener-Fresenius-Stiftung “Key-Project” grant (Project 2015_A125). Y.K. was further supported by the TRR259 (Project 397484323), and S.P. and N.J. by the International Max Planck Research School for Genome Science, part of the GAUSS/GGNB. Open Access funding enabled and organized by Projekt DEAL.
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- 2021
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