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. Scott; Jorge Ferrer; Yevgeniy Antipin; Michael Donovan; Andrew V. Uzilov; Boris Reva; Eric E. Schadt; Bojan Losic; Carmen Argmann; Andrew F. Stewart

doi:10.1038/s41467-017-00992-9

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. Scott

Jorge Ferrer, Yevgeniy Antipin, Michael Donovan, Andrew V. Uzilov, Boris Reva, Eric E. Schadt, Bojan Losic, Carmen Argmann, Andrew F. Stewart

Surgery

Research output: Contribution to journal › Article › peer-review

82 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 language	English
Article number	767
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00992-9
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
Connecticut 06520 Yale University New Haven Connecticut 06520
NIDDK Islet Integrated Distribution Program
U.S. Department of Energy Oak Ridge National Laboratory U.S. Department of Energy National Science Foundation National Energy Research Scientific Computing Center
Diabetes Research Institute Foundation
Icahn School of Medicine at Mount Sinai
Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine
Michigan Diabetes Research Center
Center for Outcomes Research and Evaluation, Yale School of Medicine
Alberta Diabetes Institute
National Institute of Diabetes and Digestive and Kidney Diseases	P30DK020593, R01DK105015, UC4DK104211, P30DK020541
UK Medical Research Council, Engineering and Physical Sciences Research Council	MR/L02036X/1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/s41467-017-00992-9

Cite this

Wang, H., Bender, A., Wang, P., Karakose, E., Inabnet, W. B., Libutti, S. K., Arnold, A., Lambertini, L., Stang, M., Chen, H., Kasai, Y., Mahajan, M., Kinoshita, Y., Fernandez-Ranvier, G., Becker, T. C., Takane, K. K., Walker, L. A., Saul, S., Chen, R., ... Stewart, A. F. (2017). Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas. Nature Communications, 8(1), Article 767. https://doi.org/10.1038/s41467-017-00992-9

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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.",

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

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Wang, H, Bender, A, Wang, P, Karakose, E, Inabnet, WB, Libutti, SK, Arnold, A, Lambertini, L, Stang, M, Chen, H, Kasai, Y, Mahajan, M, Kinoshita, Y, Fernandez-Ranvier, G, Becker, TC, Takane, KK, Walker, LA, Saul, S, Chen, R, Scott, DK, Ferrer, J, Antipin, Y, Donovan, M, Uzilov, AV, Reva, B, Schadt, EE, Losic, B, Argmann, C & Stewart, AF 2017, 'Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas', Nature Communications, vol. 8, no. 1, 767. https://doi.org/10.1038/s41467-017-00992-9

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T1 - Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas

AU - Wang, Huan

AU - Bender, Aaron

AU - Wang, Peng

AU - Karakose, Esra

AU - Inabnet, William B.

AU - Libutti, Steven K.

AU - Arnold, Andrew

AU - Lambertini, Luca

AU - Stang, Micheal

AU - Chen, Herbert

AU - Kasai, Yumi

AU - Mahajan, Milind

AU - Kinoshita, Yayoi

AU - Fernandez-Ranvier, Gustavo

AU - Becker, Thomas C.

AU - Takane, Karen K.

AU - Walker, Laura A.

AU - Saul, Shira

AU - Chen, Rong

AU - Scott, Donald K.

AU - Ferrer, Jorge

AU - Antipin, Yevgeniy

AU - Donovan, Michael

AU - Uzilov, Andrew V.

AU - Reva, Boris

AU - Schadt, Eric E.

AU - Losic, Bojan

AU - Argmann, Carmen

AU - Stewart, Andrew F.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-017-00992-9

M3 - Article

C2 - 28974674

AN - SCOPUS:85030478963

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

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ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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