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Unfolding a risk factor for type 1 diabetes
PHILADELPHIA—In what is said to be a first-of-its-kind study, Penn Medicine researchers have found that at least one risk factor for type 1 diabetes (T1D) may lie in DNA errors that can occur at times when roughly six feet of DNA is compressed into a micrometer of space in each cell nucleus via a three-dimensional folding process.
Specialized proteins decode the genetic information, reading instruction from the genome in a sequence-specific manner, as noted in a University of Pennsylvania news release (Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine [PSOM] at the University of Pennsylvania and the University of Pennsylvania Health System). But as the university noted, “What happens when a sequence variation leads to the misinterpretation of instruction, causing pathogenic misfolding of DNA inside the nucleus?”
What the researchers found in studying non-obese diabetic (NOD) mice was that changes in DNA sequence can trigger the chromosomes to misfold in a way that can put an individual at a heightened risk for T1D.
The study, titled “Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression,” was published this month in Immunity, and revealed that differences in DNA sequences dramatically changed how the DNA was folded inside the nucleus, thereby affecting the regulation of genes linked to the development of T1D.
“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,” said the study’s senior author, Dr. Golnaz Vahedi, who is an assistant professor of genetics at PSOM and a member of the Institute for Immunology and the Penn Epigenetics Institute. “Our research, for the first time, demonstrates how DNA misfolding—caused by sequence variation—contributes to the development of type 1 diabetes. With a deeper understanding, we hope to form a foundation to develop strategies to reverse DNA misfolding and change the course of type 1 diabetes.”
Until now, noted the university, little has been known about the extent to which sequence variation could cause unusual chromatin folding and, ultimately, affect gene expression. So the Penn Medicine researchers generated ultra-high resolution genomic maps to measure the three-dimensional DNA folding in T lymphocytes in two strains of mice: one diabetes-susceptible and one 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 was led by Vahedi and co-first authors Dr. Maria Fasolino, a postdoctoral fellow in immunology at PSOM, and Naomi Goldman, a graduate student at PSOM. They found that previously defined insulin-diabetes associated regions were also the most hyperfolded regions in the T cells of diabetic mice. 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 was diabetic. 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.
To put it more technically, as summarized in the paper abstract by the authors, “We generated high-resolution maps of linear and 3D genome organization in thymocytes of NOD mice, a model of type 1 diabetes (T1D), and the diabetes-resistant C57BL/6 mice. Multi-enhancer interactions formed at genomic regions harboring genes with prominent roles in T cell development in both strains. However, diabetes risk-conferring loci coalesced enhancers and promoters in NOD, but not C57BL/6 thymocytes. 3D genome mapping of NODxC57BL/6 F1 thymocytes revealed that genomic misfolding in NOD mice is mediated in cis. Moreover, immune cells infiltrating the pancreas of humans with T1D exhibited increased expression of genes located on misfolded loci in mice. Thus, genetic variation leads to altered 3D chromatin architecture and associated changes in gene expression that may underlie autoimmune pathology.”
After establishing the where the chromatin is misfolded in mice, researchers sought to study gene expression in humans. Through a collaboration with the Human Pancreas Analysis Program, they discovered that a type of homologous gene in humans also demonstrated increased expression levels in immune cells infiltrating the pancreas of human.
“While much more work is needed, our findings push us closer to a more mechanistic understanding of the link between genetics and autoimmune diseases—an important step in identifying factors that influence our risk for developing conditions, like type 1 diabetes,” Vahedi stated.
T1D is an autoimmune disease, so there is also the possibility that these findings may aid in understanding and treatment of other disease that occur when the body’s immune system attacks and destroys healthy organs, tissues and cells, such as rheumatoid arthritis and inflammatory bowel disease.