Over 1% of our DNA is made up of repeated sequences, which equals tens of thousands of short repeat tracts. Most repeat sequences are stable in length, but a small subset tend to expand or contract in length during processes such as DNA replication and repair. Over 30 human neurodegenerative disorders are associated with DNA repeat instability, including fragile X syndrome, Huntington’s disease, and Friedreich’s ataxia. For the disease-associated repeats, healthy individuals have a “normal” number of repeats, while those with the disease have repeats expanded beyond a threshold length. Researchers have long sought to understand why some DNA repeats are prone to expansion, while others are not.
The 3D arrangement of DNA impacts how information encoded by the DNA is “read” and used by the cell. To explore whether DNA folding plays a role in repeat instability, 4DN Program-funded researcher Dr. Jennifer Phillips-Cremins and her team analyzed the folding pattern of unstable regions of DNA repeats. They found that nearly all the repeat sequences associated with human disease are located at the boundaries between discreet 3D regions of the genome. To explore this in the context of human disease, they created genome folding maps around the FMR1 gene, the gene associated with fragile X syndrome, in samples from patients and healthy individuals. In samples from patients (which contained expanded repeats) they found misfolding at the expanded repeat tracts disrupted the boundary between domains, leading to the FMR1 gene being turned off. This study shows that regions of DNA repeats associated with human diseases can localize to genome domain boundaries and can disrupt 3D genome structure and gene function. Improved understanding of the link between DNA repeat instability and genome folding can aid in development of treatments for repeat expansion disorders.
References
- Disease-Associated Short Tandem Repeats Co-Localize with Chromatin Domain Boundaries. Sun, JH, Zhou, L, Emerson, DJ, Phyo, SA, Titus, KR, Gong, W, Gilgenast, TG, Beagan, JA, Davidson, BL, Tassone, F, and Phillips-Cremins, JE. Cell 175, 38-40. September 2018.
- Chromatin Domains Go on Repeat in Disease. Bruneau, BG and Nora, EP. Cell 175:1, 224-238. September 2018.
- In the News: Penn Researchers: Class of Neurological Disorders Share 3D Genome Folding Pattern, Science Magazine
