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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 .

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