In conclusion, our results showed a distinct DNA methylation profile across DM1 tissues and uncovered a novel, dual epigenetic signature involving a gain of DNA methylation in the flanking region of the CTG expansion, accompanied by specific DNA demethylation in the DMPK gene body of DM1 muscle samples, which provided novel insights into the epigenetic changes occurring in DM1. Here, DMPK is linked to myotonic dystrophy type 1.