Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells

摘要

class="head no_bottom_margin" id="sec1title">IntroductionMyotonic dystrophy type 1 (DM1) is an autosomal dominant muscular dystrophy that affects a wide range of body systems (DM1 [OMIM: ]). It results from a trinucleotide CTG repeat expansion (50–4,000 copies) in the 3′ UTR of the dystrophia myotonica protein kinase gene (DMPK) (). The CTG repeat region, which resides within a CpG island (CGI), commonly results in hypermethylation and the spread of heterochromatin when expanded (). Hypermethylation is largely age- and tissue-specific and does not necessarily correlate with expansion size in somatic cells of patients (). In addition, when the CTG repeats expand, they commonly result in a reduction in the expression of a neighboring gene, SIX5 (). The contribution of hypermethylation to disease pathogenesis is still not fully understood, nor is the precise mechanism by which CTG expansion leads to SIX5 reduction in cis. Using a wide range of DM1-affected human embryonic stem cell (hESC) lines, we aimed to uncover the mechanistic relationship between CTG expansion, aberrant methylation, and reduced expression of SIX5 in DM1.