A Network of MicroRNAs Acts to Promote Cell Cycle Exit and Differentiation of Human Pancreatic Endocrine Cells
iScience. 2019-11-22;21:681-694.
- Abstract
- Pancreatic endocrine cell differentiation is orchestrated by the action of well-described transcription factors that operate in a gene regulatory network to activateendocrine 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 overexpression experiments, and network modeling approaches using data from crosslinking immunoprecipitation with high-throughput sequencing (CLIP-seq), RNA sequencing (RNA-seq), and assays for chromatin accessibility and state. We find that out of 13 endocrine-enriched miRNAs, Let-7g, Let-7a, miR-200a, and miR-375 have the highest 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. We show that Let-7g, Let-7a, miR-200a, and miR-375 induce cell cycle exit and promote endocrine cell differentiation when expressed in human embryonic stem cell (hESC)-derived pancreatic progenitors. Our study delineates the role of miRNAs in human endocrine cell differentiation through a system-wide approach and identifies miRNAs that could facilitate endocrine cell programming of hESCs or endocrine reprogramming of other cell types.
- Consortium data used in this publication
- NOTE: For TSTSR081148 (ATAC-seq), only sample 1 and sample 2 have been used
- Datasets
- TSTSR682564, TSTSR216390, TSTSR081148