Endocrine islet beta-cell subtypes with differential function are derived from biochemically distinct embryonic endocrine islet progenitors that are regulated by maternal nutrients

Endocrine islet beta cells comprise heterogenous cell subsets. Yet the origin, stability, and physiological significance of these subsets remain largely unknown. Using combinatorial cell lineage tracing, scRNA-seq, and DNA methylation analysis, we show here that embryonic islet progenitors with differential gene expression and DNA methylation produce stable beta-cell subtypes of different function and viability in adult mice. Differentially expressed genes, including the Myt transcription factors, voltage-gated channels, and Ca2+-sensor synaptotagmins, contribute to the functional differences of these subtypes. Maternal overnutrition, a major diabetes risk factor, reduces the proportion of endocrine progenitors of the better-functionality beta-cell subtype. Intriguingly, the gene signature that defines mouse beta-cell subtypes can reliably divide human cells into two populations, with the proportion of better-functionality beta cells reduced in diabetic donors. These results establish that some beta-cell subtypes are determined via DNA methylation in embryonic islet progenitors, which is regulated by diabetes-causing maternal factors. The implication is that modulating DNA methylation in islet progenitors can be explored to improve beta-cell function in the prevention and therapy of diabetes. Mice with a genotype of Myt1cCre; Ngn3nCre; Ai9 (MNA) will be derived via routine crossing. This allows the activation of islet progenitors that co-express Ngn3 and Myt1 to be labeled with tdTomato permanently. When MNA mice were at postnatal day 2 (P2) and 2-months, they will be used for islet isolation. Islets were then washed with Ca2+/Mg2+ free HBSS and dissociated into single cells (~3-5 minutes). They were then used for InDrop RNAseq.