DNA Methylation as a Potential Molecular Mechanism in X‐linked Dystonia‐Parkinsonism. Issue 12 (10th September 2020)

• Record Type: Journal Article
• 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
• Is Part Of: Movement disorders. Volume 35:Issue 12(2020)
• Page Start: 2220
• Page End: 2229
• Publication Date: 2020-09-10
• Subjects: X‐linked dystonia‐parkinsonism -- DNA methylation -- TAF1 -- GATA2; Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.28239
• Languages: English
• ISSNs: 0885-3185

Abstract

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