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Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice
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Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice
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Journal Article
Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice
2021
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/15
/ 45
/ Age
/ Aging
/ Animals
/ Behavior, Animal - physiology
/ Chromatin Assembly and Disassembly - genetics
/ Corpus Striatum - metabolism
/ Corpus Striatum - physiopathology
/ Gene Expression Profiling - methods
/ Humanities and Social Sciences
/ Humans
/ Huntingtin Protein - genetics
/ Huntington Disease - diagnosis
/ Huntington Disease - genetics
/ Huntington Disease - physiopathology
/ Loci
/ Mice
/ Mutation
/ Neurodegenerative Diseases - diagnosis
/ Neurodegenerative Diseases - genetics
/ Neurodegenerative Diseases - physiopathology
/ Science
