Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice

© 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.