Year: 2020
Type: article
Study design: Observational Study
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.
Source: Nature Communications
Authors: 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
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,380
Funders: U.S. Department of Health and Human Services, Vanderbilt University, University of Chicago, Juvenile Diabetes Research Foundation United States of America, Wellcome Trust, Human Islet Research Network, National Institute for Health and Care Research, National Institutes of Health, Medical Research Council, National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1099034210, G1740429162, G2145740586, Epigenetic Control of Human Beta Cell Proliferation, G3654747614, G4052331345, G426723566, G445699482, G5377200542, NIHR Senior Investigator Award, G5807023910, G5965359067, G6232356985, G814604375, G836681807, G9000106514, Robust mapping of chromatin loops from sparse or single cell Hi-C data with DeepLoop, NYR-Diabetes Research Center (NYR-DRC), STAG2 mutations and 3D genome organization in glioblastoma multiforme
OpenAlex ID: W3092722307