Genome Folded Incorrectly in Fragile X Syndrome, Other Neurological Conditions, Study Finds

The 3D folding of the genome is distorted in fragile X syndrome and other closely related neurological conditions, according to researchers from the University of Pennsylvania (UPenn).

“We’re tremendously excited to examine whether and how the 3D genome misfolding in Fragile X syndrome is causally linked to the silencing of gene expression in this disease,” study author Jennifer E. Phillips-Cremins, PhD, an assistant professor at the Perelman School of Medicine at UPenn said, in a press release.

The study, “Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries,” was published in the journal Cell.

Short tandem repeats (STRs) are short repeats formed by nucleotides (building blocks of DNA) present in a gene sequence. Healthy people have STRs of normal lengths distributed across their DNA. However, in certain neurological conditions such as fragile X syndrome, amyotrophic lateral sclerosis (ALS), Huntington’s disease and others, these sequences are present as trinucleotide repeats (TNR) that are unstable and can be ultra-long in length.

The presence of these TNRs can influence the expression of the genes they occupy. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

In the case of fragile X syndrome, these repeats silence the FMR1 gene, resulting in a shorter FMRP protein and related developmental problems and learning disabilities.

To tightly fit in the cell nucleus, DNA is folded into complicated 3D patterns. Now researchers have found that almost all STRs known to become unstable in diseases are located at the boundaries that separate neighboring folded domains.

“Every human individual has hundreds of thousands of short tandem repeat tracts distributed throughout their genome. The repeats exhibit wide variation in sequence, location in the gene body, normal and mutation length ranges, the cell types they affect and the phenotypes they produce,” Phillips-Cremins said. “But, for the handful of short tandem repeat tracts known to grow unstable in disease, nearly all are localized specifically to genome folding boundaries.”

By creating a high-resolution 3D folding map of the genome around the FMR1 gene from fragile X patients and comparing it with those from healthy individuals, the team observed that these boundaries were destroyed around the gene in fragile X patients who had STR expansions and FMR1 gene silencing.

The team compared their 3D genome map to a line of densely packed cities arranged in parallel and separated by stretches of highway. The highways serve as boundaries that prevent interaction between cities, which represent different domains of the genome fold.

Whether the presence of unstable tandem repeats determines the location of a boundary or vice versa remains to be explored, the team noted.

By analyzing brain tissue and B-cells from fragile X patients, the researchers found that the misfolding in the 3D genome structure corresponds to the exact location in the FMRI gene where the genetic defect and gene silencing occurs.

“This finding raises the profile of many important questions about the relationship between genome folding, repeat expansion, and gene silencing, which we hope will one day lead to insights that might inspire therapeutic options for children affected with the disease,” said study author James Sun.

“Mechanistic studies have predominantly focused on the linear DNA thus far, but we can now add a new third dimension to understanding the genetic underpinnings of TNR diseases,” Phillips-Cremins said.