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.
|State||Published - Dec 1 2020|
Bibliographical noteFunding 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.
© 2020, The Author(s).
ASJC Scopus subject areas
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Physics and Astronomy (all)