DNA misfolding linked to risk of Type 1

Genetics, is a major factor when it comes to the risk of developing autoimmune conditions, like Type 1 diabetes.

In human cells, a person’s genome – about six feet of DNA – is compressed inside the nucleus via a three-dimensional folding process. Specialized proteins decode the genetic information, reading instruction from our genome in a sequence-specific manner.

In a world first study, researchers at Penn Medicine decided to look at what would happen if there was a variation in the sequence affecting the folding pattern in the nucleus and whether it would make people more susceptible to autoimmune conditions.

What they’ve found, in mice, is that changes in DNA sequence can trigger the chromosomes to misfold in a way that puts one at a heightened risk for Type 1 diabetes.

The study, published in Immunity, revealed that differences in DNA sequences dramatically changed how the DNA folded inside the nucleus, ultimately affecting the regulation–the induction or repression–of genes linked to the development Type 1 diabetes.

While we know that people who inherit certain genes have a heightened risk of developing Type 1 diabetes, there has been little information about the underlying molecular factors that contribute to the link between genetics and autoimmunity.

This research, demonstrates how DNA misfolding–caused by sequence variation–contributes to the development of Type 1 diabetes. With this deeper understanding, it’s hoped it will be possible to reverse DNA misfolding and change the course of Type 1 diabetes.”

Autoimmune conditions, which affect millions of people worldwide, and occur when the body’s immune system attacks and destroys healthy organs, tissues and cells. There are more than 80 types of autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, and Type 1 diabetes.

In Type 1 diabetes, the pancreas stops producing insulin, the hormone that controls blood glucose levels. White blood cells called T lymphocytes play a significant role in the destruction of insulin-producing pancreatic beta cells.

Until now, little has been known about the extent to which sequence variation could cause unusual chromatin folding and, ultimately, affect gene expression. In this study, Penn Medicine researchers generated ultra-high resolution genomic maps to measure the three-dimensional DNA folding in T lymphocytes in two strains of mice: a diabetes-susceptible and diabetes-resistant mouse strain. The two strains of mice have six million differences in their genomic DNA, which is similar to the number of differences in the genetic code between any two humans.

The Penn team, found that previously defined insulin-diabetes associated regions were also the most hyperfolded regions in the T cells of mice with diabetes. Researchers then used a high-resolution imaging technique to corroborate the genome misfolding in diabetes-susceptible mice. Importantly, they found the change in folding patterns occurred before the mouse developed the condition. Researchers suggest that the observation could serve as a diagnostic tool in the future if investigators are able to identify such hyperfolded regions in the T cells of humans.

While much more work is needed, the findings are pushing the team closer to a more mechanistic understanding of the link between genetics and autoimmune conditions. An important step in identifying factors that influence the risk for developing Type 1 diabetes.

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