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J Clin Invest. 2019 Jan 2;129(1):209-214. doi: 10.1172/JCI99170. Epub 2018 Nov 26.

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

Author information

1
Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
2
Department of Genetics, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
3
Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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.

KEYWORDS:

Beta cells; Diabetes; Endocrinology; Epigenetics

Comment in

PMID:
30352048
PMCID:
PMC6307972
DOI:
10.1172/JCI99170
[Indexed for MEDLINE]
Free PMC Article

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