Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2021

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

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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.
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Origin : Publication funded by an institution

Dates and versions

cea-03428640 , version 1 (17-11-2021)

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Attribution - CC BY 4.0

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Rafael Alcalá-Vida, Jonathan Seguin, Caroline Lotz, Anne Molitor, Ibai Irastorza-Azcarate, et al.. Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice. Nature Communications, 2021, 12 (1), pp.364. ⟨10.1038/s41467-020-20605-2⟩. ⟨cea-03428640⟩
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