# The role of HNF4a in maintaining intestinal epithelial cell homeostasis in the presence of microbes

> **NIH NIH F31** · DUKE UNIVERSITY · 2021 · $38,009

## Abstract

Abstract
Loss of homeostatic relationships with microbiota can result in inflammatory diseases such as the inflammatory
bowel diseases (IBD). Maintaining homeostasis with microbiota is predicated on the ability of host cells to adjust
their transcriptional programs in response to signals from microbiota. Intestinal epithelial cells (IECs) serve
critical roles as a barrier against microbiota. IECs perform these roles by integrating external signals into various
transcriptional programs which output appropriate physiologic responses. Hepatocyte nuclear factor 4 alpha
(HNF4A) is a nuclear receptor transcription factor (TF) that is highly expressed in the vertebrate digestive tract.
In IECs, HNF4A acts predominantly as a transcriptional activator regulating genes involved in IEC development,
barrier function, metabolism, and nutrient absorption. Genetic variants at the HNF4A gene locus and HNF4A
transcription factor binding motifs have been identified in GWAS for human IBD. Intestine specific knockout of
Hnf4a in mice results in highly penetrant spontaneous intestinal inflammation. However, it is unknown whether
this phenotype is due to intrinsic anti-inflammatory roles for HNF4A in IECs or barrier defects that result in
activation of immune cells in the lamina propria. The overall objective of this project is to understand the role of
HNF4A in maintaining homeostasis with microbiota in the intestine and in regulating microbiota-responsive
enhancers in IECs. Our lab recently made the key discovery that HNF4A activity in the IEC genome is
suppressed by microbiota in mice and zebrafish. Additionally we found that Hnf4a protects zebrafish from a
microbiota-driven transcriptional shift which correlates with transcriptional shifts seen in human IBD. We also
identified a subset of enhancers that are regulated by the microbiota in mouse IECs, which are also bound by
HNF4A. However the role of HNF4A in maintaining intestinal homeostasis with microbiota by acting on these
enhancers is unknown. I will test the central hypothesis that HNF4A promotes intestinal homeostasis in the
presence of microbiota by mediating microbiota-induced alterations in enhancer activity across the IEC genome.
In Specific Aim 1, I will derive a mouse strain lacking Hnf4a in IECs (Hnf4aΔIEC) into germ free (GF) conditions to
test the role of microbiota in the intestinal inflammation phenotype of this mouse model of IBD. Additionally, I will
generate enteroid cultures from primary IECs of these mice to study the role of HNF4A in mediating IEC intrinsic
responses to microbiota in vitro. In Specific Aim 2, I will define the role of HNF4A at microbiota responsive
enhancers using GF and ex-GF conventionalized (CV) Hnf4aΔIEC mice and wild-type controls. The outcomes of
this work will provide innovative in vivo genetic evidence establishing the role of HNF4A as a mediator of IEC
transcriptional programs protective against microbiota-driven intestinal inflammation. This research addresses a
c...

## Key facts

- **NIH application ID:** 10136433
- **Project number:** 5F31DK121392-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Cecelia Kelly
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,009
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136433

## Citation

> US National Institutes of Health, RePORTER application 10136433, The role of HNF4a in maintaining intestinal epithelial cell homeostasis in the presence of microbes (5F31DK121392-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136433. Licensed CC0.

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