Aberrant methylation underlies insulin gene expression in human insulinoma
Esra Karaköse, Huan Wang, William B. Inabnet, Rajesh V. Thakker, Steven K. 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
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.