Dnmt1 activity is dispensable in ?-cells but is essential for ?-cell homeostasis.

ABSTRACT: In addition to ?-cells, pancreatic islets contain ?- and ?-cells, which respectively produce glucagon and somatostatin. The reprogramming of these two endocrine cell types into insulin producers, as observed after a massive ?-cell ablation in mice, may help restoring a functional ?-cell mass in type 1 diabetes. Yet, the spontaneous ?-to-? and ?-to-? 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 ?- and ?-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 ?- or ?-cells toward a ?-like fate. In addition, while Dnmt1 was dispensable for the development of these two cell types, we noticed a gradual loss of ?-, but not ?-cells in adult mice. Finally, we found that Ezh2 inactivation does not enhance ?-cell plasticity, and, contrary to what is observed in ?-cells, does not impair ?-cell proliferation. Our results indicate that both Dnmt1 and Ezh2 play distinct roles in the different islet cell types.

SUBMITTER: Damond N 

PROVIDER: S-EPMC5494274 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature