# Regulation of beta-cell homeostasis by DNA methylation and hydroxymethylation.

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2021 · $432,500

## Abstract

PROJECT SUMMARY/ABSTRACT
 Diabetes has become a major public health crisis, afflicting nearly 30 million people in the United States, and
these numbers continue to rise at an alarming rate. Both type 1 and type 2 diabetes result from insulin
insufficiency, in large part due to loss of functional beta-cells. Significant research efforts are currently focused
on understanding beta-cell failure in diabetes, and developing effective therapeutic approaches to replenishing
the beta-cell deficit in diabetes. Despite significant advances in these aspects, challenges remain in development
of effective beta-cell therapies, primarily due to gaps in our current understanding of mechanisms that regulate
normal beta-cell development, function, and growth. Our recent work has identified DNA methylation as a pivotal
epigenetic mechanism that regulates beta-cell identity and function. Moreover, we found that DNA methylation
patterns defining functional beta-cell phenotype are disrupted in the diabetic beta-cells, suggesting dynamic
nature of DNA methylation. Our preliminary studies indicate that dynamic remodeling of DNA methylation (5-
methylcytosine; 5mC) via its conversion to a hydroxylated form (5-hydroxymethylcytosine; 5hmC) is essential for
beta-cell differentiation, function, and adaptive response. We hypothesize that stage-specific, appropriate
patterning of 5mC and 5hmC is critical for beta-cell homeostasis, and is disrupted in diabetes leading to beta-
cell failure. Thus, we seek to determine how enzymatic regulation of the balance between 5mC and 5hmC
governs functional beta-cell mass and affects diabetes susceptibility. We will employ mouse genetics, disease
models, human islet studies, and state-of-the-art genome wide epigenetic profiling methods to address the
following aims: In Specific Aim 1, we aim to establish the requirement of 5mC and 5hmC patterning in
differentiation of beta-cells from progenitors. Specific Aim 2 seeks to define the contribution of dynamic
remodeling of 5mC and 5hmC patterns in beta-cell replication and adaptive capacity. In Specific Aim 3, we
address if and how environmental factors like oxidative stress and metabolite variation can disrupt the beta-cell
5mC 5hmC landscape to drive beta-cell failure, and diabetes.
 The proposed studies will delineate a novel regulatory module that governs beta-cell development and
growth, and establish a fundamental regulatory paradigm that link beta-cell environment, metabolism and
epigenome. Our work is likely to have a broad and significant impact by providing novel clues to promote beta-
cell differentiation, function, and expansion towards strategies aimed at beta-cell rejuvenation and replacement
for diabetes therapy.

## Key facts

- **NIH application ID:** 10090591
- **Project number:** 5R01DK120523-03
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Sangeeta Dhawan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,500
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090591

## Citation

> US National Institutes of Health, RePORTER application 10090591, Regulation of beta-cell homeostasis by DNA methylation and hydroxymethylation. (5R01DK120523-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10090591. Licensed CC0.

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