Picture a human chromosome. Chances are, the image in your mind looks like a tiny rod in the shape of a letter “I” cinched in at the waist. Or, if you are picturing a chromosome in the process of copying itself for cell division, it looks like a letter “X” or “Y.” But what if one of those tiny letters, each of which is actually a single long string of DNA coiled and bundled up, was tied to itself end-to-end to make an “O”? This is exactly what happens in a rare and mysterious group of cytogenetic disorders known as ring chromosome syndromes.
“Seizures are the big problem for these kids,” said Nancy Spinner, PhD, chief of the division of Genomic Diagnostics at Children’s Hospital of Philadelphia and professor of Pathology and Genetics at the Perelman School of Medicine at the University of Pennsylvania. Dr. Spinner was awarded a grant from the National Institute of Neurological Disorders and Stroke (NINDS) to develop a neurological model for studying Ring 14 syndrome to better understand how gene expression changes as a result of the chromosome’s changed shape.
Amid her other full-time projects, Dr. Spinner has studied ring chromosomes since 2008 with funding from philanthropic organizations including Ring 14 International and the Ring Chromosome 20 Foundation. The NINDS grant will allow her lab to dig deeper into how these chromosomes cause impairments in children. In addition to experiencing seizures from a young age, children with Ring 14 syndrome also have intellectual disability and developmental delay.
Working in partnership with Co-Principal Investigator Stewart Anderson, MD, and collaborators Jason Mills, PhD, Laura Conlin, PhD, and Deborah McEldrew, the team is inducing the growth of cells from Ring 14 patients from induced pluripotent stem cells into neuron cells. They are using a method that matures the cells without causing them to divide and reproduce. This approach overcomes a challenge with using stem cell methods that require reproduction: Stem cells in vitro tend to self-correct the ring chromosome by losing it and replacing it with a duplication of the other copy of chromosome 14. The researchers are also attempting to develop an in vitro cerebral cortex organoid model to attempt to understand how embryonic brain development is altered by the ring chromosome.
This exploratory work should help identify which questions are most promising for further study to someday move toward targeted therapies for Ring 14 syndrome. Current knowledge is limited.
“We can see the rings, we can map the rings, we know what their gene content is, and we know that they don’t grow very well,” Dr. Spinner said. “We know some facts about them, but we don’t yet know enough about specific pathways or specific genes, so that it’s not clear how we would target them. It hasn’t been a simple answer so far.”
While these first fundamental steps toward future targeted therapies for Ring 14 syndrome are important, another, more immediate possibility in this project is that it could offer new insights into emerging scientific questions about how the physical folding and looping of DNA influences genes’ expression.
This concept of the “chromatin landscape” or “loopscape” is built on the fact that DNA inside the nucleus of a cell does not normally look like an alphabet soup of I-shaped rods — with a rare “O” in the case of ring chromosomes. Those shapes are only formed for cellular reproduction purposes as a kind of travel packaging. In the normal life of a cell, each long string of DNA is unraveled from the rod shape and re-coiled into looser bundles.
“If you take a ball of string and just ball it up in your hand, before the cat gets to it, you might think, well it’s random, which little piece of the string is going to be right next to another piece of the string, which, when pulled apart, could be a meter away,” said Dr. Anderson, a research psychiatrist at CHOP and associate professor of Psychiatry at the Perelman School of Medicine. “But it turns out that this kind of bundling of DNA is not random, and beyond that, it’s highly regulated and very specific.”
If two ends of that ball of string are tied together, as in a ring chromosome, the researchers hypothesize that that regulated and specific organization could be disrupted. Detailing the nature of those disruptions could not only help explain the mechanism of disease impairments in ring syndromes, but it could also help scientists understand more about the way DNA packaging influences gene expression in normal chromosomes.
The researchers also hope to bring more attention to ring chromosomes to rally the attention of other scientists to help.
“The families are eager to get attention because their children have serious needs and the conditions are so rare,” Dr. Spinner said. “Part of what I feel like we’re doing when we talk about this among scientists and clinicians is proselytizing. We’re trying to expose people to an interesting problem.”