The most prevalent form of myotonic dystrophy is caused by the expansion of a CTG triplet repeat in agene-rich region of chromosome 19 at the DM1 locus. The CTG repeat is in the non-coding region of the DMPK gene and adjacent to the regulatory region of the neighboring SIX5 gene. Its expansion alters the processing of the DMPK RNA, suppresses expression of the adjacent SIX5 gene, and produces a mutant RNA with an expanded CUG repeat. Our broad and long-term goal is to identify the normal role of the CTG repeats and associated CTCF binding sites at the DM1 locus. Our broad hypothesis is that these elements regulate regional gene expression through combination of insulator activity and regional chromatin organization.
Our specific aims will:
(Aim 1) Test the hypothesis that the combination of CTCF binding sites and CTG repeats insulate the DMPK promoter from the SIX5 enhancer, and that loss of this insulator function causes the congenital form of DM.
(Aim 2) Test the alternative hypotheses that CTG-mediated chromatin condensation occurs through the recruitment of specific chromatin modifying factors, or, alternatively, occurs through tight structural packaging of the nucleosomes in the repeat sequence.
(Aim 3) Test the hypothesis that the positioning of a nucleosome by the CTG repeat is critical to the function of the DM1 insulator and contributes to regulating regional promoter usage and gene silencing. The significance of this proposal is that we will determine the role of CAG/CTG repeat sequences in organizing the structure and expression of the human genome. The health relatedness is that understanding the normal role of CTG/CAG repeats in the genome will give new insight into their role in generating tissue specific diseases.
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