Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas

Huan Wang, Aaron Bender, Peng Wang, Esra Karakose, William B. Inabnet, Steven K. Libutti, Andrew Arnold, Luca Lambertini, Micheal Stang, Herbert Chen, Yumi Kasai, Milind Mahajan, Yayoi Kinoshita, Gustavo Fernandez-Ranvier, Thomas C. Becker, Karen K. Takane, Laura A. Walker, Shira Saul, Rong Chen, Donald K. ScottJorge Ferrer, Yevgeniy Antipin, Michael Donovan, Andrew V. Uzilov, Boris Reva, Eric E. Schadt, Bojan Losic, Carmen Argmann, Andrew F. Stewart

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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 languageEnglish (US)
Article number767
JournalNature communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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