# Epigenetic Regulation by FoxO1 in Pancreatic Beta Cells

> **NIH NIH K01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $153,652

## Abstract

Project Summary
Over the last 30 years, diabetes has become a pandemic. Type 2 diabetes is the most common form of
diabetes, and pancreatic β cell failure is pivotal in the pathogenesis of this metabolic disorder. Restoring β cell
function has taken center stage in developing therapeutics to “cure” diabetes, through inducing β cell
proliferation, re-differentiation, and regeneration. However, the quality and quantity of “β cell” obtained are less
than ideal. One critical aspect to facilitate these processes to generating “perfect” β cell is to understand the
epigenetic changes involved in β cell formation and maintenance. More and more evidence suggests that
histone modification and chromatin remodeling play critical roles in β cell development, cell fate commitment,
proliferation, and regeneration. Key β cell transcription factor FoxO1 is required to maintain β cell maturity.
Ablation of FoxO1 in β cells leads to β cell dedifferentiation, a process where mature β cells lose their identity
and ability to produce and secret insulin. In healthy β cells, FoxO1 is inactive and resides in the cytoplasm. In
response to stressors, such as aging and multiparity, FoxO1 translocates into the nucleus, and elicits
transcriptional networks to defend β cell health. In advanced type 2 diabetes, FoxO1 disappears from β cells
as a result of increased degradation, leading to metabolic inflexibility and paving the way for dedifferentiation.
However, whether the protective role of FoxO1 against β cell failure involves maintaining the epigenomic
landscape has not been studied. The proposed studies will fill the gap of knowledge between FoxO1,
epigenetics, functional genomics, and diabetes. The PI presented preliminary data to establish a role of FoxO1
in epigenetics with RNAseq and histone modification ChIPseq (i.e., H3K4me3, H3K27me3, and H3K27ac)
using FAC sorted β cells in β cell-specific FoxO1 KO mice. The PI will continue to build the integrative
regulatory map of FoxO1 in pancreatic β-cell with Hi-C, DNA methylation, and FoxO1 ChIPseq. H3K27ac motif
analysis and RNA profiling suggest an imbalanced regulation between FoxO1 and Hnf4α, therefore, the PI will
perform glucose clamps, glucose tolerance test, glucose- and arginine-stimulated insulin secretion in isolated
islets, and RNAseq using β cell-specific FoxO1 and Hnf4α double KO mice to determine the epistasis of
FoxO1 and Hnf4α. The PI will also functionally characterize FoxO1 targets to identify genes of therapeutic
interest. The tailored research training and career development activities will assist the PI to achieve her career
goals: becoming an independent academic investigator and advancing the field of diabetes research.

## Key facts

- **NIH application ID:** 9957055
- **Project number:** 5K01DK114372-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Taiyi Diana Kuo
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $153,652
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957055

## Citation

> US National Institutes of Health, RePORTER application 9957055, Epigenetic Regulation by FoxO1 in Pancreatic Beta Cells (5K01DK114372-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9957055. Licensed CC0.

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