DNA methylation study of Huntington\u2019s disease and motor progression in patients and in animal models

Ake T Lu,Seung Kwak,X William Yang,Richard Z Chen,Megan Grant ,Jim Rosinski,Jian Chen,C Simon Bawden,Pritika Narayan,Peter Langfelder,Giovanni Coppola,Alicia Preiss,Thomas Vogt ,Nan Wang,Darren G Monckton ,Russell G Snell,Marc Ciosi,Skye R Rudiger,Jeff Aaronson,Hilary A Wilkinson ,Afroditi Chatzi,Timothy A Hore ,Alastair Maxwell,Steve Horvath

doi:10.1038/s41467-020-18255-5

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.

Highlights

Huntington’s disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes
Our methylation study datasets derive from three species: (I) a total of 2164 human samples across blood, lymphoblast, and fibroblast tissues collected from five datasets, (II) a total of 112 mouse tissues measured on two platforms (reduced representation bisulfite sequencing (RRBS) and a custom methylation array), and (III) 168 blood samples from sheep
Apart from studying the effect of HTT mutation status on DNA methylation (DNAm) levels, we tested the hypothesis that methylation levels in blood-derived DNA are predictive of motor progression in manifest HD cases

Summary

Introduction

Huntington’s disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. HD is one of several polyglutamine disorders (including spinal cerebellar ataxias types 1, 2, 3, 6, and 7, spinal and bulbar muscular atrophy, and dentatorubral-pallidoluysian atrophy) that are caused by the expansion of unstable CAG trinucleotide repeats[1] Since these disorders exhibit distinct patterns of neuronal loss and clinical manifestation, the differential pathogenesis of polyglutamine disorders may be due to differences in polyglutamine protein context or the host protein function. DNA (de)methylation in an HTT gene context has been investigated in transgenic animal models[9] It is not yet known whether HD is associated with significant DNAm changes in other human tissues and in transgenic animal models. Blood DNAm levels of select genomic loci are associated with motor score progression among manifest HD patients

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Conclusion