Figure 2.

Regulatory role of DNA methylation in beta cell homeostasis: Pancreas morphogenesis requires intact maintenance methylation activity of Dnmt1 in Pdx1+ pancreatic progenitors, and loss of Dnmt1 in pancreatic progenitors leads to pancreatic atrophy. Specification of different endocrine lineages from the Neurog3+ endocrine progenitors involves the DNA methylation dependent regulation of the expression of lineage-specific transcription factors. The endocrine progenitors that co-express Myt1, are marked by high expression of Dnmt1 and hypermethylation of the enhancer region of Arx, a key alpha cell lineage determinant. This leads to repression of Arx and commitment of the Neurog3+ Myt1+ sub-population to beta cell lineage, while the Neurog3+ Myt1- sub-population acquires alpha cell lineage. Functional maturation of beta cells is neonatal life depends on DNA methylation patterning of genes involved in metabolism and replication. The fully differentiated beta cell phenotype is guarded by maintenance methylation through replication, and loss of Dnmt1 in beta cells leads to their trans-differentiation into alpha cells. The proliferative capacity and function of beta cell changes with age, and involves age dependent changes in the beta cell methylome.