A network of microRNAs acts to promote cell cycle exit and differentiation of human pancreatic endocrine cells

Pancreatic endocrine cell differentiation is orchestrated by transcription factors that operate in a gene regulatory network to activate endocrine lineage genes and repress lineage-inappropriate genes. MicroRNAs (miRNAs) are important modulators of gene expression, yet their role in endocrine cell differentiation has not been explored system-wide. Here we characterize miRNA-regulatory networks active in human endocrine cell differentiation by combining small RNA sequencing, miRNA overexpression experiments, and network modeling approaches. This analysis identifies Let-7g, Let-7a, miR-200a, and miR-375 as endocrine-enriched miRNAs with high impact on driving endocrine differentiation-associated gene expression changes. These miRNAs target different sets of transcription factors, which converge on a network of genes involved in cell cycle regulation. When expressed in human embryonic stem cell-derived pancreatic progenitors these miRNAs induce cell cycle exit and promote endocrine cell differentiation. Our study delineates the role of miRNAs in human endocrine cell differentiation and identifies miRNAs that could facilitate endocrine cell reprogramming.