Establishment of beta cell heterogeneity via differential CpG methylation atNnat

AbstractBeta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. The molecular mechanisms through which beta cell hierarchy is established remain poorly understood. The neuronatin (Nnat) gene is imprinted in mice and humans and is required for normal insulin synthesis and secretion. Here, we demonstrate thatNnatis differentially expressed in a discrete beta cell population in a developmental-stage and DNA methylation (DNMT3A)-dependent manner. Explored in mice expressing eGFP from a bacterial artificial chromosome-expressed transgene, NNAT+cells displayed a discrete transcriptome, and appear to represent a beta cell population specialised for insulin production. Correspondingly, highly connected ‘hub’ cells were less abundant in the NNAT+population. These findings demonstrate that differential DNA methylation atNnatrepresents a novel means through which beta cell heterogeneity is established.