title: Dnmt1 activity is dispensable in δ-cells but is essential for α-cell homeostasis.
abstract: In addition to β-cells, pancreatic islets contain α- and δ-cells, which respectively produce glucagon and somatostatin. The reprogramming of these two endocrine cell types into insulin producers, as observed after a massive β-cell ablation in mice, may help restoring a functional β-cell mass in type 1 diabetes. Yet, the spontaneous α-to-β and δ-to-β 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 α- and δ-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 α- or δ-cells toward a β-like fate. In addition, while Dnmt1 was dispensable for the development of these two cell types, we noticed a gradual loss of α-, but not δ-cells in adult mice. Finally, we found that Ezh2 inactivation does not enhance α-cell plasticity, and, contrary to what is observed in β-cells, does not impair α-cell proliferation. Our results indicate that both Dnmt1 and Ezh2 play distinct roles in the different islet cell types.
authors.affiliation: Department of Genetic Medicine & Development, Faculty of Medicine, University of Geneva, 1 Rue Michel-Servet, 1211 Geneva 4, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland; Centre facultaire du diabète, University of Geneva, Geneva, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Damond
authors.affiliation: Department of Genetic Medicine & Development, Faculty of Medicine, University of Geneva, 1 Rue Michel-Servet, 1211 Geneva 4, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland; Centre facultaire du diabète, University of Geneva, Geneva, Switzerland.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Thorel
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, CA 94305, United States; Department of Medicine, Stanford, CA 94305, United States.
authors.forename: Seung K
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Genetic Medicine & Development, Faculty of Medicine, University of Geneva, 1 Rue Michel-Servet, 1211 Geneva 4, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland; Centre facultaire du diabète, University of Geneva, Geneva, Switzerland. Electronic address: pedro.herrera@unige.ch.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
mesh_terms: D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000172:deficiency / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000172:deficiency; D004789:Enzyme Activation; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis; D051379:Mice; D019864:Somatostatin-Secreting Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619381:Dnmt1 protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse
keywords: Beta-cell regeneration; Dnmt1; Ezh2; Pancreatic islet; α-Cells; δ-Cells