Journal article
Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1
A Weber, SC Schwarz, J Tost, D Trümbach, P Winter, F Busato, P Tacik, AC Windhorst, M Fagny, T Arzberger, C McLean, JC van Swieten, J Schwarz, D Vogt Weisenhorn, W Wurst, T Adhikary, DW Dickson, GU Höglinger, U Müller
Nature Communications | NATURE PORTFOLIO | Published : 2018
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. P..
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Awarded by CurePSP
Funding Acknowledgements
We gratefully acknowledge technical support of Claudia Rohrsheim, Michaela Weis, and Stefanie Teschler (RT-qPCR, pyrosequencing), Monica Castanedes-Casey (immunohistochemistry), and Drs. Melissa Murray and Amanda Serie (Aperio technology). We thank Drs. Eilis Hannon and Jonathan Mill (University of Exeter Medical School) for the mQTL data of the adult prefrontal cortex. We also thank Drs. Per Hoffmann and Stefan Herms for advice on data analysis. Dr. Hong Xu is acknowledged for his help with DLX1 siRNA and tau overexpression experiments. We are indebted to Dr. Ellen Gelpi and Dr. Laura Molina at the Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS, Barcelona, for data and sample procurement. We thank Dr. Hagen Scherb (Institute of Computational Biology, Helmholtz Center Munich, Germany) for the support regarding statistical questions. This work was supported by a grant (#518-14) from CurePSP (to G.U.H., and U.M.), a German Federal Ministry of Education and Research (BMBF)-and French National Research Agency (ANR)-funded project on "Epigenomics of Parkinson's disease" (O1KU1403A/ ANR-13-EPIG-0003-05 EpiPD to G.U.H., J.T. and U.M.), the BMBF-funded project "HitTau" (01EK1605A to G.U.H.), the Deutsche Forschungsgemeinschaft (DFG, HO2402/6-2 & Munich Cluster for Systems Neurology SyNergy) (to G.U.H.), the NOMIS foundation (FTLD project to G.U.H.), the German Science Foundation Collaborative Research Center (CRC) 870 and the Helmholtz Portfolio Theme "Supercomputing and Modeling for the Human Brain" (SMHB) (to W.W., D.T. and D.V.W.), and the Bayerisches Staatsministerium fur Bildung und Kultus, Wissenschaft und Kunst within Bavarian Research Network "Human Induced Pluripotent Stem Cells" (ForIPS) (to G.U.H., S.C.S., W.W. and D.V.W.).