TY  - JOUR
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
TI  - Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1.
JO  - Nature Communications
VL  - 9
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2020-06431
SP  - 2929
PY  - 2018
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.
KW  - Aged
KW  - Aged, 80 and over
KW  - DNA Methylation: genetics
KW  - Epigenesis, Genetic: genetics
KW  - Female
KW  - Homeodomain Proteins: genetics
KW  - Homeodomain Proteins: metabolism
KW  - Humans
KW  - Male
KW  - Supranuclear Palsy, Progressive: genetics
KW  - Supranuclear Palsy, Progressive: pathology
KW  - Transcription Factors: genetics
KW  - Transcription Factors: metabolism
KW  - tau Proteins: genetics
KW  - tau Proteins: metabolism
KW  - Distal-less homeobox proteins (NLM Chemicals)
KW  - Homeodomain Proteins (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30050033
C2  - pmc:PMC6062504
DO  - DOI:10.1038/s41467-018-05325-y
UR  - https://pub.dzne.de/record/140109
ER  -