Lu, A. T. et al. (2020) DNA methylation study of Huntington's disease and motor progression in patients and in animal models. Nature Communications, 11, 4529. (doi: 10.1038/s41467-020-18255-5) (PMID:32913184) (PMCID:PMC7484780)
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Abstract
Although Huntington’s disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10−7) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10−26). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10−8) and in the transgenic sheep model (p = 2.4 × 10−88). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p < 10−7) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10−9), GRIK4 (p = 3.0 × 10−8), and COX4I2 (p = 6.5 × 10−8). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Maxwell, Mr Alastair and Monckton, Professor Darren and Chatzi, Ms Afroditi and Ciosi, Dr Marc |
Authors: | Lu, A. T., Narayan, P., Grant, M. J., Langfelder, P., Wang, N., Kwak, S., Wilkinson, H., Chen, R. Z., Chen, J., Bawden, C. S., Rudiger, S. R., Ciosi, M., Chatzi, A., Maxwell, A., Hore, T. A., Aaronson, J., Rosinski, J., Preiss, A., Vogt, T. A., Coppola, G., Monckton, D., Snell, R. G., Yang, X. W., and Horvarth, S. |
College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
Journal Name: | Nature Communications |
Publisher: | Nature Research |
ISSN: | 2041-1723 |
ISSN (Online): | 2041-1723 |
Copyright Holders: | Copyright © The Author(s) 2020 |
First Published: | First published in Nature Communications 11(1):4529 |
Publisher Policy: | Reproduced under a Creative Commons Licence |
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