TY - JOUR AU - Ou, Kristy AU - Yu, Ming AU - Moss, Nicholas G. AU - Wang, Yue J. AU - Wang, Amber W. AU - Nguyen, Son C. AU - Jiang, Connie AU - Feleke, Eseye AU - Kameswaran, Vasumathi AU - Joyce, Eric F. AU - Naji, Ali AU - Glaser, Benjamin AU - Avrahami, Dana AU - Kaestner, Klaus H. T1 - Targeted demethylation at the CDKN1C/p57 locus induces human β cell replication PY - 2019/01/02/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI99170 VL - 129 IS - 1 UR - https://doi.org/10.1172/JCI99170 SP - 209 EP - 214 PB - The American Society for Clinical Investigation ER -