# Mechanisms Driving Metabolic Shifts in the Intestinal Epithelium

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2024 · $389,859

## Abstract

Cells of intestinal epithelium do not exhibit a uniform metabolic state. Metabolic shifts accompany
transitions during adult stem-crypt-villus homeostasis. Metabolic shifts also occur in response to injury and in
colon cancer. The long term goal of this research is to define targetable metabolic regulatory processes to treat
diseases and disorders of the intestine. The immediate goal of this proposal is to define the regulatory
mechanisms that govern metabolic shifts during the epithelial cell lifespan.
 OX-PHOS gene expression levels are high in intestinal stem cells, low in crypts, and highest in villus.
Dynamic expression of OX-PHOS genes parallels the metabolic transitions of the epithelium. However, the
mechanisms regulating cellular metabolism during epithelial cell transitions in the intestine are unclear. We
have generated new mouse models that identify transcription factors contributing to epithelial metabolism.
 Aim 1 of the proposed studies will drill down to identify how the transcription factor, YY1, promotes
expression of genes that drive the electron transport chain. We will test the hypothesis that YY1 regulates
enhancer-promoter chromatin looping to promote expression of these key genes required for mitochondrial
respiration. We will also test the hypothesis that YY1 function differs in intestinal stem cells versus in their
progeny in crypts or in villus enterocytes. State-of-the-art epigenomic and proteomic assays will be employed
in the context of novel mouse models. We expect these regulatory mechanisms are important to drive
metabolic shifts that occur upon exposure to low oxygen environments during tissue damage/regeneration or in
oncogenesis. Therefore, we will also investigate these regulatory mechanisms in regenerative foci after tissue
damage to discern whether YY1 controls the metabolic shifts that accompany tissue regeneration.
 Aim 2 will look at regulation of an important energy source for mitochondrial respiration – fatty acid
oxidation. We will test the hypothesis that HNF4 transcription factors promote fatty acid oxidation to support
intestinal stem cell renewal. A combination of metabolomics, epigenomics, and organoid-based assays will be
employed, using novel mouse models. We will further test the hypothesis that the Estrogen-Related Receptor
is an important and novel partner factor of HNF4, and that together, HNF4 and ESRRA shape the response of
the intestinal epithelium in response to a change in dietary fat. To our knowledge, these studies would provide
the first link between the core intestinal transcription factor regulatory networks and the metabolic state
required for intestinal stemness. Excess dietary fat increases risk for obesity and colon cancer. Our studies will
move the field forward in linking how diet and metabolites can intersect with the transcriptional regulatory
mechanisms of the intestinal epithelium. Together, these studies will reveal how metabolic transitions are
regulated in the intestin...

## Key facts

- **NIH application ID:** 10848198
- **Project number:** 5R01DK126446-04
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** MICHAEL P. VERZI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $389,859
- **Award type:** 5
- **Project period:** 2021-09-23 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848198

## Citation

> US National Institutes of Health, RePORTER application 10848198, Mechanisms Driving Metabolic Shifts in the Intestinal Epithelium (5R01DK126446-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10848198. Licensed CC0.

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