How Does a Glitch in Genome Folding Lead to Disease?

The sequence of bases (As, Cs, Gs, and Ts) that make up our DNA matters: it is what determines our genetic blueprint, which in turn determines many of our characteristics. Often within the genome, a certain sequence of bases will repeat over and over. While this is usually harmless, sometimes the repeats start to erroneously expand for unknown reasons, which can cause diseases like Huntington’s, ALS, fragile X syndrome, and various movement disorders.

In a new study published in Cell and led by NYSCF – Robertson Stem Cell Investigator and Assistant Professor of Bioengineering and Genetics at the University of Pennsylvania Jennifer Phillips-Cremins, PhD, researchers made some surprising discoveries about where harmful repeat expansions occur in the genome and how the folding of our genome plays into this process.

If you were to take all the DNA out of one of your cells and stretch it from floor to ceiling, it would be about 2 meters tall. For all 2 meters of that DNA to fit into the nucleus of a cell (which is roughly the same width as a single strand of hair), it needs to crumple up and make itself compact. Once it does this, certain segments of DNA located closely to each other will start to interact. The way the genome folds changes to regulate gene expression in different conditions and cell types, and new sequencing technologies have allowed scientists to measure DNA’s folding properties.

Dr. Phillips-Cremins’ team wanted to figure out what causes these unstable repeat expansions, so they took a closer look at the very few places in the genome where they are known to occur. What makes specific locations susceptible to instability, whereas hundreds of thousands of repeat sequences across the genome are not known to grow unstable? they wondered. Surprisingly, they observed that the repeat expansions tended to occur at boundaries demarcated by genome folding patterns – specifically, at boundaries with a higher density of Cs and Gs, known as CpG islands.

To investigate how genome folding patterns differ in repeat expansion disorders, they examined tissue from patients with fragile X syndrome (the most common form of heritable intellectual disability and autism). Patients with fragile X syndrome are known to have a repeat expansion on FMR1—a gene necessary for developing the connections between neurons that help them send signals. The researchers found that the 3D genome was severely misfolded around the pathologically silenced FMR1 gene in brain tissue from patients with fragile X syndrome compared to healthy individuals (i.e. where the repeat expansion occurred, aberrant genome folding also occurred). Although repeat expansion disorders are traditionally studied from the perspective of the linear genome, these findings suggest that the way our genome folds in 3D could play a critical role in repeat instability. Therefore, preventing genome misfolding could be a possible new route to treatment for the 30 disorders caused by unstable repeat expansions.

Dr. Phillips-Cremins is excited to explore the possible cause and effect link between the 3D structure of our genome and human neurological disease in the near future, and she is grateful that the NYSCF – Robertson Investigator Program allows her to pursue this unexpected connection.

“We are now obsessed with understanding the causal relationship between repeat expansion, boundaries, and 3D genome integrity,” she says. “Our results shed light on the locations of the genome where pathologic repeat expansions can occur, suggesting that the 3D organization of our genome might play a role in genome integrity that was unknown before this study. We are immensely grateful to NYSCF for its support, which gave us the flexibility to pursue this new line of research and make this surprising breakthrough, and we are hopeful it will someday inspire new treatment approaches.”