Dnmt1 activity is dispensable in δ-cells but is essential for α-cell homeostasis

In addition to beta-cells, pancreatic islets contain alpha- and delta-cells, which respectively produce glucagon and somatostatin. The reprogramming of these two endocrine cell types into insulin producers, as observed after a massive beta-cell ablation in mice, may help restoring a functional beta-cell mass in type 1 diabetes. Yet, the spontaneous alpha-to-beta and delta-to-beta conversion processes are relatively inefficient in adult animals and the underlying epigenetic mechanisms remain unclear. Several studies indicate that the conserved chromatin modifiers DNA methyltransferase 1 (Dnmt1) and Enhancer of zeste homolog 2 (Ezh2) are important for pancreas development and restrict islet cell plasticity. Here, to investigate the role of these two enzymes in alpha- and delta-cell development and fate maintenance, we genetically inactivated them in each of these two cell types. We found that loss of Dnmt1 does not enhance the conversion of alpha- or delta-cells toward a beta-like fate. In addition, while Dnmt1 was dispensable for the development of these two cell types, we noticed a gradual loss of alpha-, but not delta-cells in adult mice. Finally, we found that Ezh2 inactivation does not enhance alpha-cell plasticity, and, contrary to what is observed in beta-cells, does not impair alpha-cell proliferation. Our results indicate that both Dnmt1 and Ezh2 play distinct roles in the different islet cell types. (C) 2017 Elsevier Ltd. All rights reserved.