Targeted demethylation at the CDKN1C/p57 locus induces human β cell replication

Kristy Ou, Ming Yu, Nicholas G. Moss, Yue J. Wang, Amber W. Wang, Son C. Nguyen, Connie Jiang, Eseye Feleke, Vasumathi Kameswaran, Eric F. Joyce, Ali Naji, Benjamin Glaser, Dana Avrahami, Klaus H. Kaestner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

The loss of insulin-secreting β cells is characteristic among type I and type II diabetes. Stimulating proliferation to expand sources of β cells for transplantation remains a challenge because adult β cells do not proliferate readily. The cell cycle inhibitor p57 has been shown to control cell division in human β cells. Expression of p57 is regulated by the DNA methylation status of the imprinting control region 2 (ICR2), which is commonly hypomethylated in Beckwith-Wiedemann syndrome patients who exhibit massive β cell proliferation. We hypothesized that targeted demethylation of the ICR2 using a transcription activator-like effector protein fused to the catalytic domain of TET1 (ICR2-TET1) would repress p57 expression and promote cell proliferation. We report here that overexpression of ICR2-TET1 in human fibroblasts reduces p57 expression levels and increases proliferation. Furthermore, human islets overexpressing ICR2-TET1 exhibit repression of p57 with concomitant upregulation of Ki-67 while maintaining glucose-sensing functionality. When transplanted into diabetic, immunodeficient mice, the epigenetically edited islets show increased β cell replication compared with control islets. These findings demonstrate that epigenetic editing is a promising tool for inducing β cell proliferation, which may one day alleviate the scarcity of transplantable β cells for the treatment of diabetes.

Original languageAmerican English
Article numberCI99170
JournalJournal of Clinical Investigation
Volume129
Issue number1
DOIs
StatePublished - 2 Jan 2019

Bibliographical note

Funding Information:
We would like to thank the Kaestner lab for helpful suggestions and discussions. This work was funded by the National Heart, Lung, and Blood Institute (NHLBI) grant 2T32HL007954-16 (to KO), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants U01-DK089529 and R01-DK088383 (to KHK). This research was performed using resources and/or funding provided by the NIDDK-supported Human Islet Research Network (HIRN, RRID:SCR_014393; https://hirnetwork.org; UC4 DK104119) to KHK, DA, and BG. We acknowledge support of the Islet Cell Biology Core and Functional Genomics Core of Penn’s Diabetes Research Center (P30-DK019525).

Publisher Copyright:
© 2019 American Society for Clinical Investigation. All rights reserved.

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