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

Rafael Alcalá-Vida, Jonathan Seguin, Caroline Lotz, Anne M. Molitor, Ibai Irastorza-Azcarate, Ali Awada, Nezih Karasu, Aurélie Bombardier, Brigitte Cosquer, Jose Luis Gomez Skarmeta, Jean-Christophe Cassel, Anne-Laurence Boutillier, Thomas Sexton and Karine Merienne ()
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Rafael Alcalá-Vida: University of Strasbourg
Jonathan Seguin: University of Strasbourg
Caroline Lotz: University of Strasbourg
Anne M. Molitor: Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC)
Ibai Irastorza-Azcarate: Berlin Institute of Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine
Ali Awada: University of Strasbourg
Nezih Karasu: Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC)
Aurélie Bombardier: University of Strasbourg
Brigitte Cosquer: University of Strasbourg
Jose Luis Gomez Skarmeta: CSIC-Universidad Pablo de Olavide-Junta de Andalucía
Jean-Christophe Cassel: University of Strasbourg
Anne-Laurence Boutillier: University of Strasbourg
Thomas Sexton: Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC)
Karine Merienne: University of Strasbourg

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20605-2

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