SRA

Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however, establishing these age-dependent changes in humans has been challenging. Here we describe a multimodal strategy for isolating pancreatic endocrine and exocrine cells from children and adults to identify age-dependent gene expression and chromatin changes on a genomic scale. These profiles revealed distinct proliferative and functional states of islet alpha-cells or beta-cells, and histone modifications underlying age-dependent gene expression changes. Expression of SIX2 and SIX3, transcription factors without prior known functions in the pancreas and linked to fasting hyperglycemia risk, increased with age specifically in human islet beta-cells. SIX2 and SIX3 were sufficient to enhance insulin content or secretion in immature beta-cells. Our work provides a unique resource to study human-specific regulators of islet cell maturation and function. Overall design: For this study we purified primary human pancreatic cells from juvenile and adult donors and analyzed the chromatin landscape using ChIP-Seq assays.