by Leigh MacMillan

In the developing pancreas, seemingly equivalent progenitor cells differentiate into the four types of hormone-positive islet cells: alpha, beta, gamma and delta. Insulin-secreting beta cells are destroyed in type 1 diabetes, and understanding how beta cells develop could lead to new cellular or regenerative therapeutic strategies for diabetes.

Ken Lau, PhD, Guoqiang Gu, PhD, and colleagues have now discovered that epigenetic “marks” on the DNA promoters of specific genes bias certain pancreatic progenitor cells toward maturing into different endocrine cell types.

The investigators used single-cell RNA sequencing, trajectory analysis and combinatorial lineage tracing to define the transcriptional and epigenetic states of pancreatic progenitor cells. They found that progenitor cells co-expressing the genes Neurog3 and Myt1 have higher levels of methylation (an epigenetic mark) in the Arx gene promoter, which drives them to become insulin-producing beta cells.

The findings, reported in Developmental Cell, demonstrate that promoter methylation is the earliest mark that distinguishes pancreatic progenitor cell identity.

This research was supported by grants from the National Institutes of Health (DK065949, DK103831, CA095103, MD007586).