DNA Methylation as a Potential Molecular Mechanism in X‐linked Dystonia‐Parkinsonism

• Published in: Movement disorders Vol. 35; no. 12; pp. 2220 - 2229
• Main Authors: Krause, Christin, Schaake, Susen, Grütz, Karen, Sievert, Helen, Reyes, Charles Jourdan, König, Inke R., Laabs, Björn‐Hergen, Jamora, Roland Dominic, Rosales, Raymond L., Diesta, Cid Czarina E., Pozojevic, Jelena, Gemoll, Timo, Westenberger, Ana, Kaiser, Frank J., Klein, Christine, Kirchner, Henriette
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.12.2020; Wiley Subscription Services, Inc
• Subjects: Basal ganglia; Bisulfite; Brain diseases; Central nervous system diseases; CpG islands; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - genetics; Dystonia; Dystonic Disorders; Epigenetics; Fibroblasts; GATA2; Gene regulation; Genetic Diseases, X-Linked; Histone Acetyltransferases - metabolism; Humans; Immunoprecipitation; Leukocytes; Movement disorders; Peripheral blood; Pluripotency; Prospective Studies; Reporter gene; Ribonucleic acid; RNA; Stem cells; TAF1; TATA-Binding Protein Associated Factors - genetics; TATA-Binding Protein Associated Factors - metabolism; Transcription Factor TFIID - genetics; Transcription Factor TFIID - metabolism; X‐linked dystonia‐parkinsonism; DNA methylation; X-linked dystonia-parkinsonism; GATA2; TAF1
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.28239

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