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

doi:10.1038/s41467-018-05325-y

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

Neuroscience

Research output: Contribution to journal › Article › peer-review

7 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 language	English (US)
Article number	2929
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05325-y
State	Published - Dec 1 2018

ASJC Scopus subject areas

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

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10.1038/s41467-018-05325-y

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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

Weber, A, Schwarz, SC, Tost, J, Trümbach, D, Winter, P, Busato, F, Tacik, P, Windhorst, AC, Fagny, M, Arzberger, T, McLean, C, van Swieten, JC, Schwarz, J, Vogt Weisenhorn, D, Wurst, W, Adhikary, T, Dickson, DW, Höglinger, GU & Müller, U 2018, 'Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1', Nature communications, vol. 9, no. 1, 2929. https://doi.org/10.1038/s41467-018-05325-y

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title = "Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1",

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.",

author = "Axel Weber and Schwarz, {Sigrid C.} and J{\"o}rg Tost and Dietrich Tr{\"u}mbach and Pia Winter and Florence Busato and Pawel Tacik and Windhorst, {Anita C.} and Maud Fagny and Thomas Arzberger and Catriona McLean and {van Swieten}, {John C.} and Johannes Schwarz and {Vogt Weisenhorn}, Daniela and Wolfgang Wurst and Till Adhikary and Dickson, {Dennis W.} and H{\"o}glinger, {G{\"u}nter U.} and Ulrich M{\"u}ller",

note = "Funding Information: We gratefully acknowledge technical support of Claudia R{\"o}hrsheim, 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{\textquoteright}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 {\textquoteleft}{\textquoteleft}Supercomputing and Modeling for the Human Brain{\textquoteright}{\textquoteright} (SMHB) (to W.W., D.T. and D.V.W.), and the Bayerisches Staatsministerium f{\"u}r 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.). Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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doi = "10.1038/s41467-018-05325-y",

language = "English (US)",

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T1 - Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1

AU - Weber, Axel

AU - Schwarz, Sigrid C.

AU - Tost, Jörg

AU - Trümbach, Dietrich

AU - Winter, Pia

AU - Busato, Florence

AU - Tacik, Pawel

AU - Windhorst, Anita C.

AU - Fagny, Maud

AU - Arzberger, Thomas

AU - McLean, Catriona

AU - van Swieten, John C.

AU - Schwarz, Johannes

AU - Vogt Weisenhorn, Daniela

AU - Wurst, Wolfgang

AU - Adhikary, Till

AU - Dickson, Dennis W.

AU - Höglinger, Günter U.

AU - Müller, Ulrich

N1 - Funding Information: We gratefully acknowledge technical support of Claudia Röhrsheim, 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 für 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.). Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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

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