The molecular program underlying infrequent replication of pancreatic β-cells remains largely inaccessible. Using transgenic mice expressing green fluorescent protein in cycling cells, we sorted live, replicating β-cells and determined their transcriptome. Replicating β-cells upregulate hundreds of proliferation-related genes, along with many novel putative cell cycle components. Strikingly, genes involved in β-cell functions, namely, glucose sensing and insulin secretion, were repressed. Further studies using single-molecule RNA in situ hybridization revealed that in fact, replicating β-cells double the amount of RNA for most genes, but this upregulation excludes genes involved in β-cell function. These data suggest that the quiescence-proliferation transition involves global amplification of gene expression, except for a subset of tissue-specific genes, which are "left behind" and whose relative mRNA amount decreases. Our work provides a unique resource for the study of replicating β-cells in vivo.
Bibliographical noteFunding Information:
This study was supported by grants from JDRF, Beta Cell Biology Consortium/Human Islet Research Network, the Leona M. and Harry B. Helmsley Charitable Trust, the European Research Commission (ERC consolidator grant), the European Union Seventh Framework Programme (241883), the Britain Israel Research and Academic Exchange Partnership (BIRAX), the Diabetes Onderzoek Nederland (DON) Foundation, the Israel Science Foundation and I-CORE Program of The Israel Science Foundation #41.11, the European Research Council (BetaToBeta), the National Institute of Diabetes and Digestive and Kidney Diseases, and the Alex U. Soyka Pancreatic Cancer Research Program (to Y.D.). A.H. was supported by a postdoctoral fellowship from JDRF. A.E. was supported by the Israel Science Foundation (grant 1361/14). This study was also supported in part by a grant from the United States Agency for International Development's American Schools and Hospitals Abroad Program for the upgrading of the Hebrew University Medical School Flow Cytometry Laboratory.
© 2016 by the American Diabetes Association.