Differences in our DNA have major influences on how our genomes function, but how

IGVF researchers are also examining how genes and regulatory elements may be forming networks of interrelated parts and how genomic variation behave in specific cell types and phenotypes.

Hannah Carter, Ph.D., an associate professor at the University of California, San Diego, is part of a research group taking a network-level approach focusing on specialized cells in the pancreas called beta cells.

Beta cells make insulin to help convert sugar in the blood to an energy source for the body. In people with diabetes, the body stops making and/or stops responding to insulin, causing high blood sugar levels. Over time, high blood sugar levels can damage organs and lead to complications such as strokes, heart attacks and kidney damage.

Dr. Carter's group studies a beta cell model not only because beta cells are relevant to diabetes but also because researchers can observe the dynamic nature of insulin production.

"The changes in insulin levels are on a short timescale that is easy to study," says Dr. Carter. "It's a tightly regulated process that can be affected by a number of different factors, from genomic variation to diet to cellular stress."

A collaborative group of UC San Diego colleagues that includes Maike Sander, M.D., Bing Ren, Ph.D. and Kyle Gaulton, Ph.D., are using pancreatic cells in tiny, three-dimensional tissue cultures, known as organoids, to study how genomic variants in different contexts can impact how much insulin is produced. To simulate different environmental conditions such as inflammation and cellular stress, the researchers expose the organoids to different chemicals or small proteins and then observe the effects. Together, the researchers are working on ways to identify a network of interrelated parts of the genome that fine-tune insulin levels in the body.

"In addition to glucose, there are different factors that affect insulin production that are not well understood," said Dr. Carter. "It's important to study how genomic variants, genetic background and environmental factors all tie in together to accurately predict risk and come up with effective solutions to help control the disease. It's the missing piece in the diabetes puzzle."

The work being done by Dr. Carter and colleagues, along projects by other IGVF researchers using different cell types and phenotype models, aim to inform optimal strategies that can be applied to other biological systems.

Caption: Microscope images of an organoids that models pancreatic islets. Pancreatic islets are a group of cells in the pancreas that produce hormones to control blood sugar levels. The hormones include glucagon (green), insulin (red), somatostatin (white). The nuclei of the cells are blue. Image credit: Kim-Vy Nguyen-Ngoc, Ph.D., University of California, San Diego.

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