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| Item Type: | Article |
|---|---|
| Title: | Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington's disease mice |
| Creators Name: | Alcalá-Vida, R. and Seguin, J. and Lotz, C. and Molitor, A.M. and Irastorza-Azcarate, I. and Awada, A. and Karasu, N. and Bombardier, A. and Cosquer, B. and Skarmeta, J.L.G. and Cassel, J.C. and Boutillier, A.L. and Sexton, T. and Merienne, K. |
| 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. |
| Keywords: | Aging, Animal Behavior, Chromatin, Chromatin Assembly and Disassembly, Corpus Striatum, Animal Disease Models, Epigenomics, Gene Expression Profiling, Gene Expression Regulation, Huntingtin Protein, Huntington Disease, Inbred C57BL Mice, Neurodegenerative Diseases, Neurons, Trinucleotide Repeat Expansion, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 12 |
| Number: | 1 |
| Page Range: | 364 |
| Date: | 13 January 2021 |
| Official Publication: | https://doi.org/10.1038/s41467-020-20605-2 |
| PubMed: | View item in PubMed |
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