1. Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice
- Author
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Alcalá-Vida, R., Seguin, J., Lotz, C., Molitor, A.M., Irastorza-Azcarate, I., Awada, A., Karasu, N., Bombardier, A., Cosquer, B., Skarmeta, J.L.G., Cassel, J.C., Boutillier, A.L., Sexton, T., Merienne, K., Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Universidad Pablo de Olavide [Sevilla] (UPO), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-17-CE12-0027,EpiHD,Rôle des mécanismes épigénétiques dans la maladie de Huntington(2017), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), European Project: 678624,CHROMTOPOLOGY), CHDI Foundation, Agence Nationale de la Recherche (France), Centre National de la Recherche Scientifique (France), Université de Strasbourg, European Research Council, European Commission, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Anne Laurence, Boutillier, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Rôle des mécanismes épigénétiques dans la maladie de Huntington - - EpiHD2017 - ANR-17-CE12-0027 - AAPG2017 - VALID, Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine - - INRT2010 - ANR-10-LABX-0030 - LABX - VALID, Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, and Understanding and manipulating the dynamics of chromosome topologies in transcriptional control - CHROMTOPOLOGY) - 678624 - INCOMING
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Epigenomics ,Aging ,congenital, hereditary, and neonatal diseases and abnormalities ,[SDV]Life Sciences [q-bio] ,Science ,Chromatin remodelling ,Article ,Animal disease models ,mental disorders ,Histone post-translational modifications ,Animals ,Humans ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,skin and connective tissue diseases ,Neurons ,Huntingtin Protein ,Behavior, Animal ,Gene Expression Profiling ,Neurodegenerative Diseases ,Huntington's disease ,Chromatin Assembly and Disassembly ,Chromatin ,Corpus Striatum ,nervous system diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,Huntington Disease ,Gene Expression Regulation ,Cardiovascular and Metabolic Diseases ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,sense organs ,Trinucleotide Repeat Expansion - Abstract
© The Author(s) 2021., Temporal dynamics and mechanisms underlying epigenetic changes in Huntington’s disease (HD), a neurodegenerative disease primarily affecting the striatum, remain unclear. Using a slowly progressing knockin mouse model, we profile the HD striatal chromatin landscape at two early disease stages. Data integration with cell type-specific striatal enhancer and transcriptomic databases demonstrates acceleration of age-related epigenetic remodelling and transcriptional changes at neuronal- and glial-specific genes from prodromal stage, before the onset of motor deficits. We also find that 3D chromatin architecture, while generally preserved at neuronal enhancers, is altered at the disease locus. Specifically, we find that the HD mutation, a CAG expansion in the Htt gene, locally impairs the spatial chromatin organization and proximal gene regulation. Thus, our data provide evidence for two early and distinct mechanisms underlying chromatin structure changes in the HD striatum, correlating with transcriptional changes: the HD mutation globally accelerates age-dependent epigenetic and transcriptional reprogramming of brain cell identities, and locally affects 3D chromatin organization., This study was supported by CHDI foundation, Inc, the Agence Nationale de la Recherche (ANR-2017-CE12-0027), the Centre National de la Recherche Scientifique (CNRS) and the University of Strasbourg. R.A.V. was supported by post-doctoral fellowship from CHDI. J.S. and A.B. were bioinformatician and technician supported by CHDI. C.L. and A.A. were recipients of doctoral fellowships from the French government and the Association Huntington France (AHF), respectively. Work in the T.S. group is supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Starting Grant 678624 - CHROMTOPOLOGY), the ATIP-Avenir program, and the grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02. A.M.M. was supported by funds from INCA. J.-L.G.-S. was supported by the Spanish government (grant no. BFU2016- 74961-P) and the institutional grant Unidad de Excelencia María de Maeztu (no. MDM-2016-0687). I.I.-A. was supported with a FEBS long-term fellowship.
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- 2021
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