# Elucidating the Role of the Rnf20 Histone Modifier in Pancreatic Beta Cell Function and Senescence

> **NIH NIH F31** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $44,843

## Abstract

PROJECT SUMMARY
Diabetes is characterized by the loss of functional pancreatic β-cell mass. With the prevalence of diabetes
increasing across the globe, it is crucial that we develop a complete understanding of the gene regulatory
mechanisms governing the maintenance of insulin-producing β-cell identity and function. In our previous work,
we demonstrated that the Isl1 transcription factor and its histone-modifying co-regulators Rnf20 and Rnf40 are
crucial for β-cell gene expression. Recently, we observed that in mice, β-cell-specific loss of Rnf20 (Rnf20Δβ-cell)
prompts a disruption of glucose homeostasis, loss of β-cell identity gene expression, and an upregulation of cell
cycle inhibitor mRNA, p19Arf. In aging human and mouse β-cells, cell cycle inhibitors encoded by Cdkn2a,
p19Arf and p16Ink4a, are upregulated and impart a reduction in functional capacity known as senescence. While
suppression of the age-associated upregulation in Cdkn2a expression is known to reverse β-cell senescence,
the transcriptional mechanisms that repress Cdkn2a in healthy β-cells are understudied. In this proposal, I will
investigate the regulatory relationship between Rnf20 and Cdkn2a to assess whether Rnf20 mediates β-cell
senescence. My primary hypothesis is that Rnf20 protects against senescence-associated loss of β-cell
functional identity through direct regulation of the Cdkn2a locus. I will address this hypothesis with two aims. In
Aim 1, I will evaluate how the β-cell specific loss of Rnf20 affects the β-cell cycle and the appearance of the
senescence-associated secretory phenotype. I will also perform systemic senolytic treatment to determine if
targeted elimination of senescent cells rescues the glucose intolerance and reduced plasma insulin levels that
occur in Rnf20Δβ-cell mice. In Aim 2, I will determine whether Rnf20 regulates the transcription of Cdkn2a. I will
perform Chromatin Immunoprecipitation (ChIP) to assess if Rnf20 directly occupies the Cdkn2a promoter and
ATAC-seq to see if loss of Rnf20 increases Cdkn2a chromatin accessibility. Our results will increase
understanding of the transcriptional mechanisms regulating both the maintenance of β-cell identity and the
process of β-cell senescence. Additionally, our outcomes may be used to inform future diabetes therapies
through either the incorporation of Rnf20 into either β-cell differentiation protocols or as a biomarker for β-cell
health. Furthermore, the proposed research plan provides a balanced training platform wherein I will expand
both my critical thinking and technical skillset through my investigations of novel regulatory mechanisms of β-
cell homeostasis. As a trainee at the University of Alabama at Birmingham (UAB) and in UAB’s Diabetes
Research Center, I have access to a strong community of supportive faculty members to assist in the successful
completion of the proposed study. Taken together, this research and training plan is a fundamental catalyst of
my trajectory toward becoming an i...

## Key facts

- **NIH application ID:** 10823738
- **Project number:** 1F31DK137440-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Tanya H Pierre
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,843
- **Award type:** 1
- **Project period:** 2024-03-18 → 2025-03-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823738

## Citation

> US National Institutes of Health, RePORTER application 10823738, Elucidating the Role of the Rnf20 Histone Modifier in Pancreatic Beta Cell Function and Senescence (1F31DK137440-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10823738. Licensed CC0.

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