Aberrant methylation underlies insulin gene expression in human insulinoma

Esra Karakose; Huan Wang; William Inabnet; Rajesh V. Thakker; Steven Libutti; Gustavo Fernandez-Ranvier; Hyunsuk Suh; Mark Stevenson; Yayoi Kinoshita; Michael Donovan; Yevgeniy Antipin; Yan Li; Xiaoxiao Liu; Fulai Jin; Peng Wang; Andrew Uzilov; Carmen Argmann; Eric E. Schadt; Andrew F. Stewart; Donald K. Scott; Luca Lambertini

doi:10.1038/s41467-020-18839-1

Aberrant methylation underlies insulin gene expression in human insulinoma

Esra Karakose, Huan Wang, William Inabnet, Rajesh V. Thakker, Steven Libutti, Gustavo Fernandez-Ranvier, Hyunsuk Suh, Mark Stevenson, Yayoi Kinoshita, Michael Donovan, Yevgeniy Antipin, Yan Li, Xiaoxiao Liu, Fulai Jin, Peng Wang, Andrew Uzilov, Carmen Argmann, Eric E. Schadt, Andrew F. Stewart, Donald K. ScottLuca Lambertini

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

3 Scopus citations

Abstract

Human insulinomas are rare, benign, slowly proliferating, insulin-producing beta cell tumors that provide a molecular “recipe” or “roadmap” for pathways that control human beta cell regeneration. An earlier study revealed abnormal methylation in the imprinted p15.5-p15.4 region of chromosome 11, known to be abnormally methylated in another disorder of expanded beta cell mass and function: the focal variant of congenital hyperinsulinism. Here, we compare deep DNA methylome sequencing on 19 human insulinomas, and five sets of normal beta cells. We find a remarkably consistent, abnormal methylation pattern in insulinomas. The findings suggest that abnormal insulin (INS) promoter methylation and altered transcription factor expression create alternative drivers of INS expression, replacing canonical PDX1-driven beta cell specification with a pathological, looping, distal enhancer-based form of transcriptional regulation. Finally, NFaT transcription factors, rather than the canonical PDX1 enhancer complex, are predicted to drive INS transactivation.

Original language	English
Article number	5210
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18839-1
State	Published - Dec 1 2020

Bibliographical note

Funding Information:
We wish to thank Bonnie and Joel Bergstein, and Lonnie and Thomas Schwartz for their constant support of this project. We also thank the NIDDK Human Islet Research Network (HIRN), the NIDDK Integrated Islet Distribution Program, the NIDDK P-30 Einstein-Sinai Diabetes Research Center, The Human Islet and Adenoviral Core at Mount Sinai, The Dean’s Flow Cytometry CORE at Mount Sinai, Dr. Piotr Witkowski at the University of Chicago, The Alberta Diabetes Institute, and the Epigenomics Core Facility at The Weill-Cornell College of Medicine. We also thank Drs. Gary Felsenfeld and Xing Jian at the Laboratory of Molecular Biology at the NIDDK for sharing DNA data files, and Dr. Christopher Wright at Vanderbilt University for sharing his PDX1 antiserum. This work was supported by NIH/NIDDK grants R-01 DK116873, P-30 020541, and JDRF Grant 2-SRA-2017 514-S-B, and UC-4 DK098085. R.V.T. and M.S. are supported by the United Kingdom MRC program grants G9825289 and G1000467, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (R.V.T. and M.S.). R.V.T. is a Wellcome Trust Investigator and NIHR Senior Investigator.

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

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

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10.1038/s41467-020-18839-1

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Karakose, E., Wang, H., Inabnet, W., Thakker, R. V., Libutti, S., Fernandez-Ranvier, G., Suh, H., Stevenson, M., Kinoshita, Y., Donovan, M., Antipin, Y., Li, Y., Liu, X., Jin, F., Wang, P., Uzilov, A., Argmann, C., Schadt, E. E., Stewart, A. F., ... Lambertini, L. (2020). Aberrant methylation underlies insulin gene expression in human insulinoma. Nature Communications, 11(1), [5210]. https://doi.org/10.1038/s41467-020-18839-1

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title = "Aberrant methylation underlies insulin gene expression in human insulinoma",

abstract = "Human insulinomas are rare, benign, slowly proliferating, insulin-producing beta cell tumors that provide a molecular “recipe” or “roadmap” for pathways that control human beta cell regeneration. An earlier study revealed abnormal methylation in the imprinted p15.5-p15.4 region of chromosome 11, known to be abnormally methylated in another disorder of expanded beta cell mass and function: the focal variant of congenital hyperinsulinism. Here, we compare deep DNA methylome sequencing on 19 human insulinomas, and five sets of normal beta cells. We find a remarkably consistent, abnormal methylation pattern in insulinomas. The findings suggest that abnormal insulin (INS) promoter methylation and altered transcription factor expression create alternative drivers of INS expression, replacing canonical PDX1-driven beta cell specification with a pathological, looping, distal enhancer-based form of transcriptional regulation. Finally, NFaT transcription factors, rather than the canonical PDX1 enhancer complex, are predicted to drive INS transactivation.",

author = "Esra Karakose and Huan Wang and William Inabnet and Thakker, {Rajesh V.} and Steven Libutti and Gustavo Fernandez-Ranvier and Hyunsuk Suh and Mark Stevenson and Yayoi Kinoshita and Michael Donovan and Yevgeniy Antipin and Yan Li and Xiaoxiao Liu and Fulai Jin and Peng Wang and Andrew Uzilov and Carmen Argmann and Schadt, {Eric E.} and Stewart, {Andrew F.} and Scott, {Donald K.} and Luca Lambertini",

note = "Funding Information: We wish to thank Bonnie and Joel Bergstein, and Lonnie and Thomas Schwartz for their constant support of this project. We also thank the NIDDK Human Islet Research Network (HIRN), the NIDDK Integrated Islet Distribution Program, the NIDDK P-30 Einstein-Sinai Diabetes Research Center, The Human Islet and Adenoviral Core at Mount Sinai, The Dean{\textquoteright}s Flow Cytometry CORE at Mount Sinai, Dr. Piotr Witkowski at the University of Chicago, The Alberta Diabetes Institute, and the Epigenomics Core Facility at The Weill-Cornell College of Medicine. We also thank Drs. Gary Felsenfeld and Xing Jian at the Laboratory of Molecular Biology at the NIDDK for sharing DNA data files, and Dr. Christopher Wright at Vanderbilt University for sharing his PDX1 antiserum. This work was supported by NIH/NIDDK grants R-01 DK116873, P-30 020541, and JDRF Grant 2-SRA-2017 514-S-B, and UC-4 DK098085. R.V.T. and M.S. are supported by the United Kingdom MRC program grants G9825289 and G1000467, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (R.V.T. and M.S.). R.V.T. is a Wellcome Trust Investigator and NIHR Senior Investigator. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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Karakose, E, Wang, H, Inabnet, W, Thakker, RV, Libutti, S, Fernandez-Ranvier, G, Suh, H, Stevenson, M, Kinoshita, Y, Donovan, M, Antipin, Y, Li, Y, Liu, X, Jin, F, Wang, P, Uzilov, A, Argmann, C, Schadt, EE, Stewart, AF, Scott, DK & Lambertini, L 2020, 'Aberrant methylation underlies insulin gene expression in human insulinoma', Nature Communications, vol. 11, no. 1, 5210. https://doi.org/10.1038/s41467-020-18839-1

TY - JOUR

T1 - Aberrant methylation underlies insulin gene expression in human insulinoma

AU - Karakose, Esra

AU - Wang, Huan

AU - Inabnet, William

AU - Thakker, Rajesh V.

AU - Libutti, Steven

AU - Fernandez-Ranvier, Gustavo

AU - Suh, Hyunsuk

AU - Stevenson, Mark

AU - Kinoshita, Yayoi

AU - Donovan, Michael

AU - Antipin, Yevgeniy

AU - Li, Yan

AU - Liu, Xiaoxiao

AU - Jin, Fulai

AU - Wang, Peng

AU - Uzilov, Andrew

AU - Argmann, Carmen

AU - Schadt, Eric E.

AU - Stewart, Andrew F.

AU - Scott, Donald K.

AU - Lambertini, Luca

N1 - Funding Information: We wish to thank Bonnie and Joel Bergstein, and Lonnie and Thomas Schwartz for their constant support of this project. We also thank the NIDDK Human Islet Research Network (HIRN), the NIDDK Integrated Islet Distribution Program, the NIDDK P-30 Einstein-Sinai Diabetes Research Center, The Human Islet and Adenoviral Core at Mount Sinai, The Dean’s Flow Cytometry CORE at Mount Sinai, Dr. Piotr Witkowski at the University of Chicago, The Alberta Diabetes Institute, and the Epigenomics Core Facility at The Weill-Cornell College of Medicine. We also thank Drs. Gary Felsenfeld and Xing Jian at the Laboratory of Molecular Biology at the NIDDK for sharing DNA data files, and Dr. Christopher Wright at Vanderbilt University for sharing his PDX1 antiserum. This work was supported by NIH/NIDDK grants R-01 DK116873, P-30 020541, and JDRF Grant 2-SRA-2017 514-S-B, and UC-4 DK098085. R.V.T. and M.S. are supported by the United Kingdom MRC program grants G9825289 and G1000467, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (R.V.T. and M.S.). R.V.T. is a Wellcome Trust Investigator and NIHR Senior Investigator. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Human insulinomas are rare, benign, slowly proliferating, insulin-producing beta cell tumors that provide a molecular “recipe” or “roadmap” for pathways that control human beta cell regeneration. An earlier study revealed abnormal methylation in the imprinted p15.5-p15.4 region of chromosome 11, known to be abnormally methylated in another disorder of expanded beta cell mass and function: the focal variant of congenital hyperinsulinism. Here, we compare deep DNA methylome sequencing on 19 human insulinomas, and five sets of normal beta cells. We find a remarkably consistent, abnormal methylation pattern in insulinomas. The findings suggest that abnormal insulin (INS) promoter methylation and altered transcription factor expression create alternative drivers of INS expression, replacing canonical PDX1-driven beta cell specification with a pathological, looping, distal enhancer-based form of transcriptional regulation. Finally, NFaT transcription factors, rather than the canonical PDX1 enhancer complex, are predicted to drive INS transactivation.

AB - Human insulinomas are rare, benign, slowly proliferating, insulin-producing beta cell tumors that provide a molecular “recipe” or “roadmap” for pathways that control human beta cell regeneration. An earlier study revealed abnormal methylation in the imprinted p15.5-p15.4 region of chromosome 11, known to be abnormally methylated in another disorder of expanded beta cell mass and function: the focal variant of congenital hyperinsulinism. Here, we compare deep DNA methylome sequencing on 19 human insulinomas, and five sets of normal beta cells. We find a remarkably consistent, abnormal methylation pattern in insulinomas. The findings suggest that abnormal insulin (INS) promoter methylation and altered transcription factor expression create alternative drivers of INS expression, replacing canonical PDX1-driven beta cell specification with a pathological, looping, distal enhancer-based form of transcriptional regulation. Finally, NFaT transcription factors, rather than the canonical PDX1 enhancer complex, are predicted to drive INS transactivation.

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Aberrant methylation underlies insulin gene expression in human insulinoma

Abstract

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