The Islet-1 Interaction Partner Rnf20 Regulates Glucose Homeostasis and Pancreatic β-cell Identity

Diabetes is characterized by a loss of functional β-cell mass, therefore identifying factors involved in establishing and preserving β-cells is critical to combat rising diabetes incidence. While transcription factors are crucial β-cell regulators, knowledge of co-regulators facilitating gene expression is limited. Previously, we demonstrated that the Islet-1 transcription factor forms complexes with ubiquitin ligases Rnf20 and Rnf40 to regulate β-cells in vitro. Here, we investigate whether Rnf20-mediated complexes are required for β-cell function in adult islets by characterizing a novel β-cell-enriched Rnf20 knockout mouse model. Tamoxifen induction of Rnf20 recombination prompts a robust loss of histone 2B monoubiquitination (H2Bub1), imparts severe hyperglycemia, glucose intolerance, and elicits an overall reduction in insulin content. Expression of mRNAs and proteins involved in glucose stimulated insulin secretion and β-cell identity are also dysregulated in Rnf20Δβ-cell mice. Comparative analyses of the loss of either Rnf20 or Isl1 yields similar changes in the β-cell regulome, supporting that Isl1::Rnf20 complexes are critical regulators of β-cell identity and function. Isl1::Rnf20 complexes are maintained in human tissues wherein they regulate insulin expression, secretion, and content. These findings increase our understanding of key players in β-cell maintenance, which is crucial for the advancement of β-cell derivation diabetes therapeutics.