Expanded CUG Repeats Trigger Disease Phenotype And Expression Changes Through The RNAi Machinery In C. elegans.

Myotonic dystrophy type 1 (DM1) is an autosomal-dominant inherited disorder caused by the expansion of CTG repeats in the 3’ untranslated region of the DMPK gene. The RNAs bearing these expanded repeats have a range of toxic effects. Here we provide evidence from a Caenorhabditis elegans DM1 model that the RNAi machinery has a key role in causing RNA toxicity and disease phenotypes. We show that the expanded repeats systematically affect a range of endogenous genes bearing short non-pathogenic repeats and that this mechanism is dependent on the small RNA pathway. By perturbating the RNAi machinery, we could reverse the RNA toxicity effect and reduce the disease pathogenesis. Our results support a role for RNA repeats as templates (based on sequence homology) for moderate but constant gene silencing. Such a silencing effect, although small, might affect the cell steady-state over time, with diverse impacts depending on tissue, developmental stage and the type of repeat. Importantly, such a mechanism might be common among repeats and similar in human cells with different diseases.