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 - 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.
UR - http://www.scopus.com/inward/record.url?scp=85092583725&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85092583725&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-18839-1
DO - 10.1038/s41467-020-18839-1
M3 - Article
C2 - 33060578
AN - SCOPUS:85092583725
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5210
ER -