DNA Hydroxymethylation Regulates Beta-Cell Maturation and Expansion

Epigenetic mechanisms play a central role in governing functional beta-cell mass. In particular, the methylation of DNA to generate 5-methylcytosine (5mC), directed by DNA methyltransferases, has been shown to regulate the establishment and maintenance of beta-cell identity and function. While the contribution of DNA methylation to beta-cell homeostasis and diabetes pathogenesis has been studied in detail, not much is known about the role of DNA demethylation in beta-cells. Oxidative conversion of 5mC to 5-hydroxymethylcytosine (5hmC) by Ten Eleven Translocation (Tet) enzymes constitutes a key step towards active DNA demethylation. In the present study, we provide evidence that the 5hmC landscape is dynamic, and undergoes specific changes during embryonic and postnatal islet development, islet adaptation, and in diabetes. We report that the Pdx1-positive pancreatic progenitors are marked by very low 5hmC, and beta-cell differentiation and functional maturation is accompanied by a progressive increase in 5hmC. However, under conditions during adaptive beta-cell expansion as well as in diabetes 5hmC levels decline in part due to the oxidative stress. These changes in 5hmC pattern are conserved in mouse and human pancreas, and are accompanied by the changes in Tet2 levels. We show that deletion of Tet2 in the pancreatic lineage results in improved glucose tolerance and beta-cell function. Together, our data show the importance of Tet2-dependent 5hmC patterning in maintaining a differentiated beta-cell phenotype, and highlight the remodeling of beta-cell epigenetic landscape as a key component of diabetes pathogenesis.