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 and Luca Lambertini
Additional contact information
Esra Karakose: The Icahn School of Medicine at Mount Sinai
Huan Wang: Sema4
William Inabnet: The Icahn School of Medicine at Mount Sinai
Rajesh V. Thakker: University of Oxford
Steven Libutti: The Cancer Institute of New Jersey
Gustavo Fernandez-Ranvier: The Icahn School of Medicine at Mount Sinai
Hyunsuk Suh: The Icahn School of Medicine at Mount Sinai
Mark Stevenson: University of Oxford
Yayoi Kinoshita: The Icahn School of Medicine at Mount Sinai
Michael Donovan: The Icahn School of Medicine at Mount Sinai
Yevgeniy Antipin: The Icahn School of Medicine at Mount Sinai
Yan Li: Case Western Reserve University
Xiaoxiao Liu: Case Western Reserve University
Fulai Jin: Case Western Reserve University
Peng Wang: The Icahn School of Medicine at Mount Sinai
Andrew Uzilov: The Icahn School of Medicine at Mount Sinai
Carmen Argmann: The Icahn School of Medicine at Mount Sinai
Eric E. Schadt: The Icahn School of Medicine at Mount Sinai
Andrew F. Stewart: The Icahn School of Medicine at Mount Sinai
Donald K. Scott: The Icahn School of Medicine at Mount Sinai
Luca Lambertini: The Icahn School of Medicine at Mount Sinai

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18839-1

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