1. Targeted demethylation at the CDKN1C/p57 locus induces human [beta] cell replication
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Ou, Kristy, Yu, Ming, Moss, Nicholas G., Wang, Yue J., Wang, Amber W., Nguyen, Son C., Jiang, Connie, Feleke, Eseye, Kameswaran, Vasumathi, Joyce, Eric F., Naji, Ali, Glaser, Benjamin, Avrahami, Dana, and Kaestner, Klaus H.
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Research ,Cell cycle -- Research ,Pancreatic beta cells -- Research ,Gene expression -- Research - Abstract
IntroductionIn 2014, 422 million people worldwide lived with diabetes (1). While patients with type I or severe forms of type II diabetes can manage extreme glucose excursions by administering insulin [...], The loss of insulin-secreting [beta] cells is characteristic among type I and type II diabetes. Stimulating proliferation to expand sources of [beta] cells for transplantation remains a challenge because adult [beta] cells do not proliferate readily. The cell cycle inhibitor p57 has been shown to control cell division in human [beta] 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 [beta] 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 [beta] cell replication compared with control islets. These findings demonstrate that epigenetic editing is a promising tool for inducing [beta] cell proliferation, which may one day alleviate the scarcity of transplantable [beta] cells for the treatment of diabetes.
- Published
- 2019
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