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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, Chun Zeng, Nicholas Vinckier, Allen Wang, Kim-Vy Nguyen-Ngoc, Joshua Chiou, Klaus H. Kaestner, Kelly Frazer, Andrea C. Carrano, Hung-Ping Shih, Maike Sander
doi: https://doi.org/10.1101/618330
Wen Jin
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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Francesca Mulas
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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Bjoern Gaertner
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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Yinghui Sui
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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Jinzhao Wang
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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Chun Zeng
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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Nicholas Vinckier
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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Allen Wang
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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Kim-Vy Nguyen-Ngoc
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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Joshua Chiou
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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Klaus H. Kaestner
2Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
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Kelly Frazer
3Department of Pediatrics, Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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Andrea C. Carrano
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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Hung-Ping Shih
4Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolic Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
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Maike Sander
1Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
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  • For correspondence: masander@ucsd.edu
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SUMMARY

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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 25, 2019.
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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, Chun Zeng, Nicholas Vinckier, Allen Wang, Kim-Vy Nguyen-Ngoc, Joshua Chiou, Klaus H. Kaestner, Kelly Frazer, Andrea C. Carrano, Hung-Ping Shih, Maike Sander
bioRxiv 618330; doi: https://doi.org/10.1101/618330
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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, Chun Zeng, Nicholas Vinckier, Allen Wang, Kim-Vy Nguyen-Ngoc, Joshua Chiou, Klaus H. Kaestner, Kelly Frazer, Andrea C. Carrano, Hung-Ping Shih, Maike Sander
bioRxiv 618330; doi: https://doi.org/10.1101/618330

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