Pancreatic beta cell identity is maintained by DNA methylation- mediated repression of Arx

Adult pancreatic beta cells can replicate during growth and after injury to maintain glucose homeostasis. Here we report that beta cells deficient in Dnmt1, an enzyme that propagates DNA methylation patterns during cell division, were converted to alpha cells. We identified the lineage determination gene aristaless related homeobox (Arx), as methylated and repressed in beta cells, and hypo-methylated and expressed in alpha cells and Dnmt1-deficient beta cells. We show that the methylated region of the Arx locus in beta cells was bound by methyl binding protein MeCP2 which recruited PRMT6, an enzyme that methylates histone H3R2 resulting in repression of Arx. This suggests that propagation of DNA methylation during cell division also ensures recruitment of enzymatic machinery capable of modifying and transmitting histone marks. Our results reveal that propagation of DNA methylation during cell division is essential for repression of alpha cell lineage determination genes to maintain pancreatic beta cell identity.