UNC SRP researchers create blueprint for using genomics technologies to understand mechanisms behind environmental exposure and disease outcomes
Research from UNC SRP Project 1 suggests potential therapeutic target for arsenic-associated diabetes.
A new study from Project 1 resulted in a recent publication exploring the mechanisms connecting inorganic arsenic (iAs) and diabetes.
UNC SRP trainee and lead author Jenna Todero’s research is at the interface of environmental exposures, diabetes, and genomics, studying the relationship between chronic exposure to iAs, an environmental toxin recognized as a top priority by the Agency for Toxic Substance and Disease Registry, and Type 2 diabetes. Her research was conducted under the leadership of UNC SRP Project 1 co-leaders, Praveen Sethupathy, PhD and Miroslav Styblo, PhD.
While this association is well recognized, the mechanism for this relationship remains unclear.
“Exposure to arsenic, generally through contaminated drinking water, is associated with diabetes,” Sethupathy explains. “However, exactly how this happens remains poorly understood. Our study provides a blueprint for using multiple genomics technologies to better understand how environmental exposures lead to disease in people.”
The authors of the study integrated information from three different sequencing technologies–chromatin run-on sequencing, RNA-sequencing, and small RNA-sequencing—on the pancreatic beta cells of mice, a proxy for understanding underlying mechanisms of iAs exposure and diabetes in humans. Beta cells are cells in the pancreas that produce and release insulin in response to blood sugar levels.
“This novel integrative approach led to our discovery of the abnormal activity of a specific microRNA, miR-29a, which appears to play an important role in how arsenic impairs the function of rodent pancreatic beta cells,” said Sethupathy. MiRNAs are small RNA molecules that control the expression of genes after transcription.
The study demonstrated that arsenic, and its metabolic derivative, monomethylarsenite, impair the normal ability of beta cells in mice to secrete insulin in response to glucose, a hallmark feature of diabetes. The authors identified numerous genes important in beta cell maintenance and function that are dysregulated after exposure to arsenic.
“Many of these are predicted miR-29a targets,” explained Todero. “This work justifies further functional studies of miR-29a in the beta cell after arsenic exposure, as it could be driving beta cell impairment.
As 10% of health expenses globally are spent treating diabetes, it is vital to identify mechanisms of disease onset as researchers work towards development of new and effective treatments.
“Our findings certainly motivate future work to determine whether miR-29a is equally important in human pancreatic beta cells as it appears to be in rodents,” says Sethupathy. “If it is, then it may suggest that miR-29a is a potential therapeutic target for arsenic-associated diabetes.”