Abstract
Epigenetic mechanisms, especially DNA methylation, are suggested to play a role in the age-of-onset in Huntington's disease (HD) based on studies on patient brains, and cellular and animal models. Methylation is tissue-specific and it is not clear how HD specific methylation in the brain correlates with the blood compartment, which represents a much more clinically accessible sample. Therefore, we explored the presence of HD specific DNA methylation patterns in whole blood on a cohort of HDM and healthy controls from Slovenia. We compared CpG site-specific DNA methylation in whole blood of 11 symptomatic and 9 pre-symptomatic HDM (HDM), and 15 healthy controls, by using bisulfite converted DNA on the Infinium® Human Methylation27 BeadChip microarray (Illumina) covering 27,578 CpG sites and 14,495 genes. Of the examined 14,495 genes, 437 were differentially methylated (p < 0.01) in pre-symptomatic HDM compared to controls, with three genes (CLDN16, DDC, NXT2) retaining statistical significance after the correction for multiple testing (false discovery rate, FDR < 0.05). Comparisons between symptomatic HDM and controls, and the comparison of symptomatic and pre-symptomatic HDM further identified 260 and 198 differentially methylated genes (p < 0.01), respectively, whereas the comparison of all HDM (symptomatic and pre-symptomatic) and healthy controls identified 326 differentially methylated genes (p < 0.01), however, none of these changes retained significance (FDR < 0.05) after the correction for multiple testing. The results of our study suggest that methylation signatures in the blood compartment are not robust enough to prove as valuable biomarkers for predicting HD progression, but recognizable changes in methylation deserve further research.
Highlights
Huntington’s disease (HD) is a fatal autosomal dominant neurodegenerative disorder manifested by progressive impairment of motor function, cognitive decline, and various psychiatric symptoms, beginning typically after 45 years of age [1]
Twenty mutation carriers were different in age due to presymptomatic (9 samples−4 males, 5 females, age 33.6 ± 7.26; Unified Huntington’s Disease Rating Scale (UHDRS) 0-3) and symptomatic
Microarray methylation analysis of 27,578 CpG sites covering 14,495 genes was performed on bisulfite converted DNA from whole blood of 11 symptomatic, 9 pre-symptomatic HD mutation carriers (HDM), and 15 healthy controls
Summary
Huntington’s disease (HD) is a fatal autosomal dominant neurodegenerative disorder manifested by progressive impairment of motor function, cognitive decline, and various psychiatric symptoms, beginning typically after 45 years of age [1]. Epigenetic changes in HD have been studied predominantly in the brains of patients, as well as in cell and animal models [6] In these studies, epigenetic changes have been identified to occur both in general processes such as histone acetylation and methylation [7,8,9], as well as in specific epigenetic changes, such as DNA methylation [10,11,12,13,14,15,16]. Cytosine DNA methylation (5-mC) is one of the most studied specific modifications It typically occurs at CpG sites which are enriched in regions called CpG islands [17] and is involved in gene expression silencing and regulation of splicing. This tissue-specific process is thought to be one of the main mechanisms regulating tissue-specific gene expression [18, 19]
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