6:50 PM
Sep 13, 2018
 |  BC Innovations  |  Targets & Mechanisms

Repeat offenders

Chromatin structure could provide a unified 3-D key to repeat expansion diseases

Dozens of intractable DNA repeat-driven diseases could boil down to a common problem: disrupted boundaries between chromatin domains, according to a study from the University of Pennsylvania. The results present new opportunities for diseases like fragile X syndrome and Huntington’s disease, which until now have been tackled one by one on the basis of their individual mutations and pathologies.

About 30 diseases have been identified that arise in genes containing excessive copies of tandem repeat sequences, which are defined as a series of two or more DNA bases repeated back to back.

Such repeat sequences are abundant in normal genomes, where they help regulate gene expression and have no pathological outcomes. But while most tandem repeats remain stable across generations, the disease-associated ones can undergo expansions that result in deficient gene expression, or expression of pathological versions of a gene.

In fragile X, for example, the 5’ untranslated region (UTR) of the FMR1 gene contains more than 200 CGG repeats, which silences its expression. Healthy individuals have about 30 CGG repeats, while people with 55-200 repeats are at higher risk for having offspring with further expansions -- considered as “premutation status.”

Huntington’s disease (HD) involves high numbers of CAG repeats in the HTT gene. Other examples are amyotrophic lateral sclerosis (ALS), Friedreich ataxia and early infantile epileptic encephalopathy, which result from excessive repeats of GGGGCC, GAA and GCG in the C9orf72, FXN and ARX genes, respectively.

But why some tandem repeats are prone to pathogenic expansions and others aren’t has been unclear.

In an August publication in Nature, the UPenn team pinned the answer to the genes’ chromatin structures, showing that 26 out of 27 disease-associated tandem repeats examined sit at boundaries between 3-D formations known as topologically associating domains (TADs). While the sequences are located where a boundary should be in both normal and disease states, the team used cells from fragile X patients, which contain expanded repeats, to show the boundaries are ablated in disease.

“Now we’re excited because we’re thinking, could it be possible to use topology-directed engineering ideas...

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