Myotonic Dystrophy (DM1) is caused by expansion of CTG repeats located within an insulator element at the DM1 locus. My central hypothesis is that the precise establishment of chromatin structure by wild type CTG repeats and CTCF binding sites at the DM1 insulator is critical for the maintenance of transcriptional regulation at the DM1 locus, and that CTG expansion-mediated alterations in chromatin structure and the loss of CTCF binding are critical events in the onset of myotonic dystrophy. I propose to test this central hypothesis through three interrelated specific aims: 1) determine the influence of CTG repeats, and CTG repeat expansion, on the chromatin structure of the DM1 locus, 2) determine how CTG repeats, CTG repeat expansion, and CTCF binding affect DM1 insulator function, and 3) determine the contribution of CTCF binding to the DM1 insulator to the congenital DM1 phenotype using a mouse model. The long term objective of this research is to increase our understanding of the molecular mechanisms underlying the development of both adult-onset and congenital myotonic dystrophy.
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