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

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.

The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration

“…The polyglutamine expansion in the HTT protein is an indicator of early stage HD. Drastic changes in DNA methylation has been found associated with this expansion and that increased mHTT expression; resulting in declined neurogenesis, cognition, and motor function in transgenic mouse and human (Ng et al, 2013;Lu et al, 2020).…”

Roles of physical exercise in neurodegeneration: reversal of epigenetic clock

“…Similar to AD and PD, HD also exhibits an accelerated epigenetic age. Only the CpGs located in proximity (within 2 kb) to the CAG expansion in exon 1 of HTT are significantly hypermethylated in HD, which exhibit positive correlations with severe motor progression in patients [ 164 , 165 ]. Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor neuron system, which is generally caused by mutations in the chromosome 9 open reading frame ( C9orf72 ) gene [ 166 ].…”

DNA Methylation in Huntington’s Disease

“…The human epigenome shows characteristic changes during the aging process and based on altered DNA methylation patterns an epigenetic age can be calculated [ 38 ]. As HD is an age-dependent, progressive disorder several of the above detailed genome-wide DNA methylation studies asked whether mHtt induced pathogenesis alters epigenetic age [ 33 , 36 , 37 ]. Genome-wide CpG methylation analysis of 475 tissue samples from nine brain regions (Frontal lobe, Occipital lobe, Parietal lobe, Temporal lobe, Caudate nucleus, Cerebellum, Cingulate gyrus, Hippocampus, and Midbrain) indicated that epigenetic age is altered in HD in general, and this effect depended on the clinical severity of the disease: HD cases without the most severe Vonsattel (VS) grade 4 [ 39 ] samples showed a significant epigenetic age acceleration effect in the parietal and frontal lobes and the cingulate gyrus, increasing biological age by several years.…”

“…Furthermore, epigenetic age acceleration showed a positive correlation with age of motor onset, but a negative correlation with CAG repeat length, the latter effect is most likely related to the decelerated epigenetic aging in VS grade 4 samples that had the longest CAG repeats in the study [ 33 ]. Similarly, significant epigenetic age acceleration was shown in manifest HD cases compared to controls by analyzing blood samples from the Enroll-HD and Registry-HD studies, and epigenetic age acceleration showed positively correlated with the progression of motor symptoms [ 36 ]. In contrast to the findings above no significant differences in DNA methylation age between human HD and control forebrain cortical samples were found by De Sousa et al in a smaller sample set [ 17 ].…”

“…Although direct evidence of altered Kdm5d DNA methylation in the progeny of HDACi 4b treated mice was not presented this finding suggests a role for DNA methylation in transgenerational effects in HD and suggests an intricate interplay of different epigenetic mechanisms (i.e., histone acetylation and methylation, and DNA methylation) in mHtt induced transcriptional dysregulation [ 65 ]. Considering that the HTT locus itself is differentially methylated in HD [ 36 ], such transgenerational epigenetic effects might also influence HTT expression and the phenomenon of anticipation (earlier manifestation of the disease in subsequent generations) that is primarily caused by expansion of the disease-causing CAG repeat [ 67 ].…”