Introduction and Objective: Pancreatic islets maintain glucose homeostasis, with diabetes mellitus arising from autoimmune destruction (T1D) or dysregulation (T2D) of insulin-producing pancreatic β-cells. While exogenous insulin treats T1D, transplanted stem cell-derived islet-like cells may offer improved glycemic control with fewer long-term complications. However, a better understanding of pancreas and islet development is needed for successfully generating these cells. Pancreas organogenesis begins with the emergence of multipotent progenitor cells (MPCs), which differentiate into endocrine (islet) or exocrine lineages. This process is orchestrated by transcription factors (TF) that require interacting transcriptional co-regulators, but these relationships are poorly understood. We identified the co-regulator Rnf20, an E3 ubiquitin ligase that monoubiquitinates histone H2B (“H2Bub1”), interacts with the Islet-1 TF to maintain adult β-cell function. We hypothesized Rnf20 is required during pancreatic development by supporting gene regulation governing differentiation. Methods: A pancreas-specific (Pdx1) Cre-Lox approach deleted Rnf20 in embryonic mice. Developmental Rnf20 loss was evaluated using immunofluorescence to examine TF, H2Bub1, and hormone expression. Neonatal unfed/fed blood glucose and plasma insulin were measured. Results: Rnf20-deficient neonates displayed severe pancreatic hypoplasia and dysglycemia. Early pancreatic development appeared unaffected, as suggested by the presence of MPCs. Immunofluorescence supported that Rnf20 loss also results in decreased islet hormone expression. Conclusion: Rnf20 is required for pancreas organogenesis, as loss leads to agenesis. These data support a novel role for Rnf20 during pancreas organogenesis and subsequent neonatal islet function. Disclosure C. Nelms: None. T.H. Pierre: None. S. Poole: None. C. Hunter: None. Funding R01-DK128132, T32-DK128770
NELMS et al. (Fri,) studied this question.