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DNA Methylation as a Potential Molecular Mechanism in X‐linked Dystonia‐Parkinsonism
Author(s) -
Krause Christin,
Schaake Susen,
Grütz Karen,
Sievert Helen,
Reyes Charles Jourdan,
König Inke R.,
Laabs BjörnHergen,
Jamora Roland Dominic,
Rosales Raymond L.,
Diesta Cid Czarina E.,
Pozojevic Jelena,
Gemoll Timo,
Westenberger Ana,
Kaiser Frank J.,
Klein Christine,
Kirchner Henriette
Publication year - 2020
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.28239
Subject(s) - dna methylation , parkinsonism , dystonia , biology , epigenetics , cpg site , methylation , microbiology and biotechnology , cancer research , genetics , gene expression , gene , medicine , neuroscience , disease
ABSTRACT Background X‐linked dystonia‐parkinsonism is a neurodegenerative movement disorder. The underlying molecular basis has still not been completely elucidated, but likely involves dysregulation of TAF1 expression. In X‐linked dystonia‐parkinsonism, 3 disease‐specific single‐nucleotide changes (DSCs) introduce (DSC12) or abolish (DSC2 and DSC3) CpG dinucleotides and consequently sites of putative DNA methylation. Because transcriptional regulation tightly correlates with specific epigenetic marks, we investigated the role of DNA methylation in the pathogenesis of X‐linked dystonia‐parkinsonism. Methods DNA methylation at DSC12, DSC3, and DSC2 was quantified by bisulfite pyrosequencing in DNA from peripheral blood leukocytes, fibroblasts, induced pluripotent stem cell–derived cortical neurons and brain tissue from X‐linked dystonia‐parkinsonism patients and age‐ and sex‐matched healthy Filipino controls in a prospective study. Results Compared with controls, X‐linked dystonia‐parkinsonism patients showed striking differences in DNA methylation at the 3 investigated CpG sites. Using methylation‐sensitive luciferase reporter gene assays and immunoprecipitation, we demonstrated (1) that lack of DNA methylation because of DSC2 and DSC3 affects gene promoter activity and (2) that methylation at all 3 investigated CpG sites alters DNA–protein interaction. Interestingly, DSC3 decreased promoter activity per se compared with wild type, and promoter activity further decreased when methylation was present. Moreover, we identified specific binding of proteins to the investigated DSCs that are associated with splicing and RNA and DNA binding. Conclusions We identified altered DNA methylation in X‐linked dystonia‐parkinsonism patients as a possible additional mechanism modulating TAF1 expression and putative novel targets for future therapies using DNA methylation‐modifying agents. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society