DNA methylation study of Huntington's disease and motor progression in patients and in animal models

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(1), 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
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Chatzi, Ms Afroditi and Maxwell, Mr Alastair and Monckton, Professor Darren 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 > Institute of Molecular Cell and Systems Biology
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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