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Volume 3, Issue 4
J Clin Epigenet
ISSN: 2472-1158
Epigenetics 2017
November 06-08, 2017
EPIGENETICS & CHROMATIN
November 06-08, 2017 | Frankfurt, Germany
2
nd
International Congress on
J Clin Epigenet 2017, 3:4
DOI: 10.21767/2472-1158-C1-003
DNA dysmethylation of various genes contributes to disease risk in progressive supranuclear palsy
Ulrich Müller
Institute of Human Genetics, Germany
Statement of the Problem
: Progressive Supranuclear Palsy (PSP) is a neurodegenerative tauopathy. The etiology of this
complex disorder is poorly understood. An accumulation of multiple environmental, genetic, and possibly epigenetic factors
is thought to eventually cause disease. Thus, advanced age contributes to risk as do certain polymorphisms of the genes
MAPT, STX6, EIF2AK3, and MOBP. A possible role of epigenetic changes in PSP is currently under investigation and dys-
regulation of several miRNAs has been reported. This study was performed to investigate whether DNA dys-methylation
might also contribute to disease.
Methods
: DNA was extracted from forebrains of 94 PSP patients (age at death 72±5.3 years) and 72 controls (76±7.9 years).
Methylation was studied using the Infinium 450k array of Illumina that includes more than 485,000 potentially methylated
CpG sites distributed over the entire genome. 200 ng of bisulfite-converted DNA were hybridized to the array. Arrays were
scanned and GenomeStudio software (version 2011.1; Illumina Inc., San Diego, CA) was used to measure the intensity of
DNA methylation signals on the arrays. DAVID Bioinformatics resources 6.7 were used for functional analysis of hyper- and
hypo-methylated genes. Highly significant (P<0.01) methylation differences of >1% were compiled and the location of these
differentially methylated sites was analyzed. Functional annotation clustering was performed and enrichment scores >1.3
were considered significant.
Findings
: Significant (p<0.01) methylation differences of >1% were detected at 621 sites amounting to 383 protein-coding
genes. At high stringency (p<0.01, methylation difference >5%), dys-methylated CpGs were found associated with 30 genes.
142 of the dysmethylated sites were also detected in age- and gender-matched cohorts (difference >1%, p<0.01). Disease-
specific changes were found at 59 and age-dependent methylation differences were detected at 16 CpG sites. Of the genes
dys-methylated by >5% (p<0.01) differences were disease-specific in 8 and age-dependent in 3 genes. While dysmethylation of
>5% affected one or a few CpG sites in most genes, in one, i.e. DLX1 hyper-methylation was found at multiple sites including
a CpG island in the 3´-untranslated region (UTR) of the gene. This and flanking genes (DLX2, METAP1D) are methylated in
an age-dependent manner. Among the disease-specifically dys-methylated genes, HDAC4, which might serve as a therapeutic
target, was hypo-methylated. Conclusion: The data suggest that both disease-specific and age-dependent, i.e. premature
dysmethylation of various genes contribute to PSP.