Our results may provide potential explanation: besides abnormal RNA-induced sequestration of splicing factor MBNL1 as suggested by the RNA toxicity model, local chromatin structure changes induced by the aberrant expansion of CTG repeats in 3′-untranslated region of DMPK gene first result in decreased expression of its downstream gene SIX5 (TKO SC mice); with an increasing number of repeats, the expression of its upstream gene DMWD is also affected (mimicked by QKO SC mice), leading to more severe and early onset DM1 (Supplementary information, Table S3). Here, SIX5 is linked to myotonic dystrophy type 1.