Abstract
Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the "genomic recipe" for beta cell expansion, we surveyed 38 human insulinomas to obtain insights into therapeutic pathways for beta cell regeneration. An integrative analysis of whole-exome and RNA-sequencing data was employed to extensively characterize the genomic and molecular landscape of insulinomas relative to normal beta cells. Here, we show at the pathway level that the majority of the insulinomas display mutations, copy number variants and/or dysregulation of epigenetic modifying genes, most prominently in the polycomb and trithorax families. Importantly, these processes are coupled to co-expression network modules associated with cell proliferation, revealing candidates for inducing beta cell regeneration. Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery.
| Original language | English |
|---|---|
| Article number | 767 |
| Journal | Nature Communications |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2017 |
Bibliographical note
Publisher Copyright:© 2017 The Author(s).
Funding
We wish to thank the following people and organizations for their support: The Foundation for Diabetes Research, the Murray-Heilig Fund in Molecular Medicine at the University of Connecticut; the NIDDK Islet Integrated Distribution Program (IIDP); Dr Tatsuya Kin at the University of Edmonton and Dr Patrick MacDonald at the Alberta Diabetes Institute; The Biorepository and Pathology Core, the Flow Cytometry Center for Research Excellence, and the computational resources and staff expertize provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai; The Human Islet and Adenoviral Core (HIAC) of the Einstein-Sinai Diabetes Research Center (DRC); The Epigenomics Core of Weill-Cornell Medicine. We thank Drs Ronald Tamler, Erika Villanueva for helping to obtain insulinomas; Drs Yanan Cao and Guang Ning of the Shanghai Key Laboratory for sharing data; Mr Justin Bellizzi for technical assistance; and Drs Alexandra Nica, Philippe Halban, Manolis Dermatzakis, and Drs David Blodgett and David Harlan for sharing their normal beta cell transcriptome data with us. We thank Drs Adolfo Garcia-Ocaña and Rupangi Vasavada for continued discussion of these findings, Dr Jordi Ochando for help with human beta cell flow cytometry, Dr Christopher Newgard for sharing the RIP1-mini-CMV enhancer promoter for construction of the RIP1-ZsGreen adenovirus, and Ms. Aye Moe and Drs Wei-Yi Cheng, Ke Hao and Antonio di Narzo for bioinformatic support. Finally, we apologize to the authors whose important work we were unable to cite because of reference number limitations. This work was supported by NIDDK grants UC4 DK104211 and P-30 DK 020541.
| Funders | Funder number |
|---|---|
| Alberta Diabetes Institute | |
| U.S. Department of Energy Oak Ridge National Laboratory U.S. Department of Energy National Science Foundation National Energy Research Scientific Computing Center | |
| Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine | |
| NIDDK Islet Integrated Distribution Program | |
| National Institute of Diabetes and Digestive and Kidney Diseases | UC4 DK104211, P30DK020541 |
| Diabetes Research Institute Foundation | |
| Center for Outcomes Research and Evaluation, Yale School of Medicine | |
| Icahn School of Medicine at Mount Sinai | |
| Connecticut 06520 Yale University New Haven Connecticut 06520 | |
| Michigan Diabetes Research Center |
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
