A Network of microRNAs Acts to Promote Cell Cycle Exit and Differentiation of Human Pancreatic Endocrine Cells
Wen Jin,
Francesca Mulas,
Bjoern Gaertner,
Yinghui Sui,
Jinzhao Wang,
Ileana Matta,
Chun Zeng,
Nicholas Vinckier,
Allen Wang,
Kim-Vy Nguyen-Ngoc,
Joshua Chiou,
Klaus H. Kaestner,
Kelly A. Frazer,
Andrea C. Carrano,
Hung-Ping Shih,
Maike Sander
Affiliations
Wen Jin
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Francesca Mulas
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Bjoern Gaertner
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Yinghui Sui
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Jinzhao Wang
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Ileana Matta
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Chun Zeng
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Nicholas Vinckier
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Allen Wang
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Kim-Vy Nguyen-Ngoc
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Joshua Chiou
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Klaus H. Kaestner
Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
Kelly A. Frazer
Department of Pediatrics, Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Andrea C. Carrano
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Hung-Ping Shih
Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolic Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
Maike Sander
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA; Corresponding author
Summary: Pancreatic endocrine cell differentiation is orchestrated by the action of 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 systematically explored. Here we characterize miRNA-regulatory networks active in human endocrine cell differentiation by combining small RNA sequencing, miRNA over-expression, and network modeling approaches. Our analysis identified Let-7g, Let-7a, miR-200a, miR-127, and miR-375 as endocrine-enriched miRNAs that drive endocrine cell differentiation-associated gene expression changes. These miRNAs are predicted to target different transcription factors, which converge on 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. : Molecular Mechanism of Gene Regulation; Molecular Network; Endocrinology; Stem Cells Research Subject Areas: Molecular Mechanism of Gene Regulation, Molecular Network, Endocrinology, Stem Cells Research
