Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1

Weber, Axel; Schwarz, Sigrid C.; Tost, Jörg; Truembach, Dietrich; Winter, Pia; Busato, Florence; Tacik, Pawel; Windhorst, Anita C.; Fagny, Maud; Arzberger, Thomas; McLean, Catriona; Swieten, John C. van; Schwarz, Johannes; Weisenhorn, Daniela Vogt; Wurst, Wolfgang; Adhikary, Till; Dickson, Dennis W.; Höglinger, Günter U. und Müller, Ulrich (2018): Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1. In: Nature Communications, Bd. 9, 2929

Abstract

Genetic, epigenetic, and environmental factors contribute to the multifactorial disorder progressive supranuclear palsy (PSP). Here, we study epigenetic changes by genome-wide analysis of DNA from postmortem tissue of forebrains of patients and controls and detect significant (P < 0.05) methylation differences at 717 CpG sites in PSP vs. controls. Four-hundred fifty-one of these sites are associated with protein-coding genes. While differential methylation only affects a few sites in most genes, DLX1 is hypermethylated at multiple sites. Expression of an antisense transcript of DLX1, DLX1AS, is reduced in PSP brains. The amount of DLX1 protein is increased in gray matter of PSP forebrains. Pathway analysis suggests that DLX1 influences MAPT-encoded Tau protein. In a cell system, overexpression of DLX1 results in downregulation of MAPT while overexpression of DLX1AS causes upregulation of MAPT. Our observations suggest that altered DLX1 methylation and expression contribute to pathogenesis of PSP by influencing MAPT.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2041-1723
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198