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Targeted demethylation at the CDKN1C/p57 locus induces human β cell replication
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Targeted demethylation at the CDKN1C/p57 locus induces human β cell replication
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Journal Article
Targeted demethylation at the CDKN1C/p57 locus induces human β cell replication
2019
Overview
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.
Publisher
American Society for Clinical Investigation
Subject
/ Beckwith-Wiedemann Syndrome - metabolism
/ Beckwith-Wiedemann Syndrome - pathology
/ Cyclin-Dependent Kinase Inhibitor p57 - biosynthesis
/ Diabetes
/ DNA
/ Genes
/ Genomes
/ Humans
/ Insulin
/ Insulin-Secreting Cells - metabolism
/ Insulin-Secreting Cells - pathology
/ Ki-67 Antigen - biosynthesis
/ Pancreas
/ Proteins
