# The DNA methylome-based regulation of functional beta-cell mass

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $396,131

## Abstract

This supplement application aims to test how maternal low-protein diet exposure during fetal development
impacts the function and viability of neurons in postnatal mouse hypothalamus and hippocampus. The
hypothesis is that intrauterine factors modulate the DNA methylomes of embryonic neuronal progenitor cells;
this methylation pattern predetermines the expression levels of key neuronal genes and therefore preset the
risk of Alzheimer’s diseases and related diseases (ADRD) in adult ages. Specifically, we will focus on the
neurons that are derived from embryonic progenitor cells that express transcription factor Neurogenin 3 (a.k.a.
Neurog3 or Ngn3). Published studies have shown that these Ngn3+ progenitors give rise to neurons in the
hypothalamus and hippocampus, whose deteriorating function is closely associated with ADRD. Thus, we will
purify embryonic Ngn3+ neural progenitor cells as well as their adult descendants in mouse brains and
examine the methylome and transcriptome of these cells. These patterns will be directly compared between
control mice and those exposed to maternal low-protein diet. In addition, immunoassays in some key candidate
genes will be conducted, including Syt1, Syt7, APP, and Tau, important for neuronal function and associated
with ADRD, respectively. Our preliminary data showing the regulation of these two candidates by DNA
methylation justify these assays. Basic behavioral assays will also used to correlate the physiological
phenotype with the DNA methylation states. Notably, these studies are parallel to what will be pursued in the
Aim 3 of the parent R01, which examines how intrauterine factors impact the methylomes/transcriptomes of
Ngn3+ islet beta-cell progenitors and the function of their adult progeny in the context of type 2 diabetes (T2D).
These supplement studies therefore rely on identical mouse models, same techniques, and similar expertise
as those proposed in the parent R01. More importantly, it has long been recognized that T2D and ADRD are
tightly linked with each other; the risks of both diseases are heavily affected by the intrauterine history. Thus,
examining the overlapping and distinct mechanisms in the development/function of Ngn3+ lineages, one in the
pancreas the other in the brain, is expected to yield potential targets to interfere with the development both
diseases.

## Key facts

- **NIH application ID:** 10287569
- **Project number:** 3R01DK125696-02S1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Guoqiang Gu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,131
- **Award type:** 3
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287569

## Citation

> US National Institutes of Health, RePORTER application 10287569, The DNA methylome-based regulation of functional beta-cell mass (3R01DK125696-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10287569. Licensed CC0.

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