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Abstract
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.
The dynamics of chromatin and transcriptional changes underlying Huntington’s disease remain poorly understood. Here the authors use a Huntington’s mouse model to profile the striatal chromatin landscape, finding that the Huntington’s mutation accelerates age-dependent epigenetic and transcriptional changes, and locally affects 3D chromatin organization.
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1 University of Strasbourg, Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), Strasbourg, France (GRID:grid.11843.3f) (ISNI:0000 0001 2157 9291); CNRS UMR 7364, Strasbourg, France (GRID:grid.4444.0) (ISNI:0000 0001 2112 9282)
2 Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), Illkirch, France (GRID:grid.420255.4) (ISNI:0000 0004 0638 2716); CNRS UMR7104, Illkirch, France (GRID:grid.420255.4) (ISNI:0000 0004 0638 2716); INSERM U1258, Illkirch, France (GRID:grid.420255.4); University of Strasbourg, Strasbourg, France (GRID:grid.11843.3f) (ISNI:0000 0001 2157 9291)
3 Berlin Institute of Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany (GRID:grid.419491.0) (ISNI:0000 0001 1014 0849)
4 CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Centro Andaluz de Biología del Desarrollo (CABD), Seville, Spain (GRID:grid.419693.0) (ISNI:0000 0004 0546 8753)