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, thereby identifying factors involved in establishing and preserving β-cell identity and function is critical for future therapies aiming to combat rising diabetes incidence. While transcription factors are crucial β-cell regulators, knowledge of the interacting co-regulators facilitating gene expression is limited. Previously, we demonstrated that the Islet-1 (Isl1) transcription factor forms complexes with histone ubiquitin ligases Rnf20 and Rnf40 to regulate β-cell gene expression and insulin secretion in vitro. Here, we investigated whether Rnf20-mediated complexes are required for β-cell function in adult islets using an adult-inducible β-cell-enriched Rnf20 knockout mouse model, termed Rnf20Δβ-cell . Tamoxifen induction of Rnf20 recombination prompted a robust loss of histone 2B monoubiquitination (H2Bub1) in β-cells and imparted severe hyperglycemia and glucose intolerance, reduced plasma insulin levels following a glucose challenge, and an overall reduction in insulin content. Expression of mRNAs and proteins involved in glucose stimulated insulin secretion (GSIS) and β-cell identity were also dysregulated in Rnf20Δβ-cell mice. Furthermore, comparative loss of either Rnf20 or Isl1 yielded a similar differential expression of numerous β-cell factors, supporting that Isl1::Rnf20 complexes and histone H2B mono-ubiquitination are critical regulators of cellular identity and function.