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

Axel Weber, Sigrid C. Schwarz, Jörg Tost, Dietrich Trümbach, Pia Winter, Florence Busato, Pawel Tacik, Anita C. Windhorst, Maud Fagny, Thomas Arzberger, Catriona McLean, John C. van Swieten, Johannes Schwarz, Daniela Vogt Weisenhorn, Wolfgang Wurst, Till Adhikary, Dennis W. Dickson, Günter U. Höglinger, Ulrich Müller

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Article number2929
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Weber, A., Schwarz, S. C., Tost, J., Trümbach, D., Winter, P., Busato, F., Tacik, P., Windhorst, A. C., Fagny, M., Arzberger, T., McLean, C., van Swieten, J. C., Schwarz, J., Vogt Weisenhorn, D., Wurst, W., Adhikary, T., Dickson, D. W., Höglinger, G. U., & Müller, U. (2018). Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1. Nature communications, 9(1), [2929]. https://doi.org/10.1038/s41467-018-05325-y