# Comprehensive characterization of HNF1A-driven beta-cell heterogeneity

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $597,761

## Abstract

PROJECT ABSTRACT
The heterogeneity of pancreatic β-cells has been reported in many studies, but the field still lacks a consensus
about its molecular signature and disease relevance. Our recent single cell multiome analysis suggested that
HNF1A is a principal driver of a T2D-associated heterogeneity among the -cells from the same individual. By
leveraging single cell Patch-seq data, we also discovered that HNF1A activity is associated with lower Na+
currents in β-cells and nominated a HNF1A target, FXYD2, as the primary mitigator. Since mutations in HNF1A
are known to cause early onset diabetes (MODY3), there is a strong likelihood that HNF1A plays a causal role
in T2D via governing -cell heterogeneity. In fact, many literatures studied HNF1A and its mutations due to the
connection to MODY3, but little is known about its role in common diabetes in the context of -cell heterogeneity.
It should be noted that although our previous work has demonstrated the power of single cell multiome to study
-cell heterogeneity, the data did not allow us to directly compare the HNF1Ahi and HNF1Alo -cell populations
due to technical difficulties. In this project we will develop new single cell multiome integration strategy to directly
survey HNF1A function in -cell heterogeneity. We will establish stem cell models to manipulate HNF1A dosage
in hESC-derived -cells, which will not only provide mechanistic insights into how HNF1A mediates MODY3 and
-cell heterogeneity, but also offer new opportunity to improve the functionality of hPSC-derived -like cells for
therapeutical benefits. We will also develop new cell line model to allow genetic and chemical screens for the
upstream regulators of HNF1A in -cells. Taken together, our project will establish a new concept linking MODY3
gene HNF1A to common diabetes in the context of -cell heterogeneity.

## Key facts

- **NIH application ID:** 10980162
- **Project number:** 2R01DK113185-06
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Yan Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $597,761
- **Award type:** 2
- **Project period:** 2018-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980162

## Citation

> US National Institutes of Health, RePORTER application 10980162, Comprehensive characterization of HNF1A-driven beta-cell heterogeneity (2R01DK113185-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10980162. Licensed CC0.

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