Epigenomic atlas answers questions about islet cell heterogeneity in type 2 diabetes

Type 2 diabetes (T2D) is a complex, multifactorial disease characterized by uncontrolled blood glucose levels. It occurs when beta cells, the insulin-producing cells of the pancreatic islet, fail to produce insulin and eventually die. Yet, the initiating event that culminates in beta cell failure remains poorly defined. Dr. Maike Sander, Director of the Pediatric Diabetes Research Center and Co-Director of the Center on Diabetes in the Institute of Engineering in Medicine at UC San Diego, is collaborating with the Center to clarify the etiology of this complex disease. Their ultimate goal is to uncover new avenues for therapeutic intervention by pinpointing the specific, cell type-specific gene regulatory programs that lead to beta cell failure.

Epigenomic techniques can be used to elucidate gene regulation in disease-relevant tissues. But ensemble, or bulk, assays ignore the substantial heterogeneity that typifies most tissues. Defining this heterogeneity can help researchers understand how cells might interact to cause pathology. “We’ve known about the functional heterogeneity of beta cells since the 1980s, but we still don’t understand the molecular logic that gives rise to this heterogeneity,” Sander explained. Does this heterogeneity reflect distinct cell subtypes?

Or cellular states along a continuum? A new, single-cell-resolved ATAC-seq atlas generated by Sander in collaboration with Dr. Kyle Gaulton (UCSD) and the Center suggests that the functional heterogeneity observed within islet cell types maps to cellular states related to hormone production and stress-related signaling. “We called them ‘states’ because we don’t know how fluid they are. Maybe they’re very stable,” Sander noted.

The single-nucleus ATAC-seq atlas and accompanying work was published in Nature Genetics. Although the work focused on pancreatic islets from healthy donors, Sander wants to create a similar atlas using diseased tissue. “Gene regulatory networks may change in disease. By mapping the epigenetics on healthy tissue, you may miss important aspects that only appear in the disease context,” Sander said.

The new single cell atlas may help clarify how islet cell states, cis-regulatory elements, and genes interact to cause T2D, but Sander cautioned that more information is needed about the role that spatial organization plays: “Understanding whether failing beta cells are located near one another, near blood vessels, or other islet cell types will help us generate new hypotheses about the early events that lead to type 2 diabetes.” Sander plans to capitalize on the Center’s Spatial Epigenomics Platform to explore this idea.

“By approaching the problem from different angles, we hope to discover the causal events that lead to beta cell failure. Then we can start figuring out how to use that information for therapeutics.”

- Dr. Maike Sander