Investigating the Molecular Mechanisms of Splicing-Perturbing Small Molecules with Massively Parallel Sequencing in a Myotonic Dystrophy 1 Model
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Myotonic dystrophy is the most common form of adult-onset muscular dystrophy and appears in two forms: myotonic dystrophy 1 (OM 1) and 2 (DM2). Both diseases arc characterized by progressive muscle degeneration, myotonia, iridescent, cataracts, and in severe cases neurodcgcncration and cardiac dysfunction. Both forms of myotonic dystrophy are caused by an expansion of repeat DNA in distinct loci in the genome. In DM1, a CTG repeat is expanded from less than 50 repeats in normal individuals to up to several thousand repeats in DM1 patients. The molecular basis of this disease relics on the transcription of these repeats from DNA into RNA. Small molecules that can specifically target the repeats at the DNA level and inhibit their transcription - and thus alleviate the disease symptoms - represent a prime target for the development of therapeutics. This study investigates the capacity of two small molecules, pentamidine and actinomycin D, to reverse the molecular symptoms of DM1 through transcriptional inhibition and provides insight into their DNA target specificity and potential mechanisms of action.