Advisor(s)

Chad Hunter

Committee Member(s)

Adam Wende
Farah Lubin
Glenn Rowe
Sushant Bhatnagar

Document Type

Dissertation

Date of Award

6-1-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Cellular and Molecular Physiology

Abstract

Diabetes is defined as a loss of functional beta cell mass. It is classically categorized into Type 1 Diabetes (T1D), immune-mediated beta cell destruction and Type 2 Diabetes, which is characterized by whole body insulin resistance alongside beta cell dysregulation. The incidence of diabetes worldwide has risen annually. Despite the presence of therapeutic interventions, diabetes’ heterogeneity can prompt ineffective glycemic control and the development of diabetes-associated comorbidities. For that reason, new approaches to glycemic control for individuals with diabetes are required. One approach to restore glucose homeostasis is beta cell replacement therapy, in which stem cells are programmed into beta-like cells and transplanted into individuals with diabetes. These therapies rely upon a well-established understanding of the molecular mechanisms defining beta cell identity and function to properly provide sustained control of blood glucose levels. This dissertation builds upon our lab’s extensive work on revealing Islet-1 (Isl1) driven transcriptional regulation of beta cell function and identity. Isl1 is a LIM homeodomain transcription factor (TF) that is critical for both endocrine pancreas development and beta cell function. We have demonstrated that Isl1 interacts with Ring Finger 20 (Rnf20) and Rnf40, which are E3 ubiquitin ligases that deposit a ubiquitin moiety on histone H2B (H2Bub1). H2B monoubiquitination precedes methylation of H3K4 and H3K79 which are the canonical activation marks Rnf20 and Rnf40 utilize to regulate gene transcription. Through in vitro experiments, we observed that Isl1 and Rnf20 share regulation of beta cell gene expression and function. The first chapter of this thesis expounds upon these initial findings with an in vivo Rnf20 knockout mouse model that further elucidates the importance of Rnf20 in regulation beta cell function. Whereas the second chapter explores the contribution of Rnf20 in the beta cell cycle, as it has previously been implicated in regulating yeast cell size control and tumorigenesis. Collectively, the works described here delineate the mechanisms by which Rnf20 works to maintain beta cell functional identity. Future studies will build upon these findings to allow for its translation into diabetes therapeutics, either through incorporation into beta cell differentiation protocols or as a biomarker of mature beta-like cells.

Keywords

Beta Cells;Diabetes;H2Bub1;Histone Modifier;Rnf20;Ubiquitin Ligase

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