TY - JOUR
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 - 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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U2 - 10.1038/s41467-018-05325-y
DO - 10.1038/s41467-018-05325-y
M3 - Article
C2 - 30050033
AN - SCOPUS:85050816717
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2929
ER -