Resetting the Epigenetic Status of the DM1 Locus

Myotonic dystrophy type 1 is a genetic disorder that causes muscle loss and weakness, affecting a wide range of body functions. The disease is caused by the repeated expansion of the three DNA code letters CTG within the gene dystrophia myotonica protein kinase DMPK. While healthy individuals have only few of these CTG repeats in the DMPK gene, patients having more than 50 of these repeats start showing symptoms. Repeat numbers can reach several thousands, and larger repeat expansions are typically associated with earlier onset and more severe disease. Molecularly, these repeat expansions affect the expression of genes that are important for muscle function. In addition, at the affected genes the repeats also cause changes to the structure of chromatin, the tight complex of DNA and associated proteins. One modification that is known to affect chromatin structure the methylation of DNA, which is often termed an epigenetic mark. Epigenetics is the scientific field that studies heritable changes to chromatin structure and gene expression in the absence of mutations to the DNA sequence. Our collaboration partner Dr. Rachel Eiges at the Shaare Zedek Medical Center in Jerusalem has shown that CTG repeat expansion causes an increase in DNA methylation at certain regions of the DMPK gene. Furthermore, she discovered that removal of the causative repeats in embryonic stem cells reverts also the epigenetic changes at the DMPK gene. In contrast, in muscle progenitor cells the DNA methylation changes persist even when the causative repeats are removed. In a joint project, we are studying the epigenetic mechanisms that upon repeat removal result in the inheritance of DNA methylation in muscle progenitors and in the removal of the marks in embryonic stem cells. My laboratory brings in a long-standing expertise in chromatin biology and epigenomics. In particular, we will develop reporter cells that allow monitoring their epigenetic status. These cells we will then use in screening approaches to identify compounds and genes involved in the maintenance and reversal of chromatin marks following repeat removal. The project thus not only has the potential to uncover novel fundamental mechanisms of epigenetic inheritance but also to contribute novel insights of relevance for future therapeutic approaches.

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