# TET1 in alcoholic liver disease progression

> **NIH NIH R21** · TULANE UNIVERSITY OF LOUISIANA · 2021 · $175,727

## Abstract

Project Summary
Chronic alcohol abuse has been linked to abnormal epigenetic modifications that affect the progression of
alcoholic liver disease (ALD) by influencing factors in controlling cell death in hepatocytes. One such factor is
5-hydroxymethylcytosine (5hmC), but there is currently little information as to how chronic alcohol consumption
affects 5hmC's regulation of cell death. Understanding how alcohol impacts 5hmC formation and consequently
cell death pathways will potentially yield therapeutic approaches towards ALD. In our preliminary studies, we
found that 5hmC expression is down-regulated in the livers of rats and mice fed with an ethanol diet as well as
in human ALD tissues. We further examined the expression levels of enzymes involved in the generation of
5hmC, which include methylcytosine dioxygenase TET1, TET2, and TET3 in ALD samples. It was found that
TET1 is significantly down-regulated in human and rodent ALD samples. We determined that using shRNA-
TET1 to knockdown TET1 in human hepatocytes significantly suppressed 5hmC formation and promoted cell
death as well as the pro-apoptotic gene, HRK. Intriguingly, the treatment of the DNA methylation inhibitor, 5-
Azacytidine, could replace the impact of TET1 knockdown on hepatocyte cell death, further suggesting the
importance of DNA methylation in TET1-mediated hepatocyte cell death. We then analyzed how TET1 down-
regulation is involved in ALD progression by using TET1 knockout mice. It was found that knockout of TET1
substantially elicited liver fibrosis, which is consequently the outcome of wound-healing in chronic liver damage.
Thus, our central hypothesis is that ethanol exposure increases hepatocyte cell death to promote ALD
progression by suppressing TET1-mediated 5hmC epigenetic changes. Our long-term objective is to clarify the
underlying mechanisms by which TET1 modulates ALD progression, and determine if TET1 is a potential
therapeutic target in ALD. Two specific aims propose to evaluate our hypothesis. In aim 1, we will examine
how TET1 modulates cell death pathways in ALD progression. We will investigate the enzymatic function of
TET1 in regulating cell death pathways by using TET1 catalytic domain, full length TET1, TET1 catalytic
domain dead mutation, and TET1 specific inhibitor. In aim 2, we will examine the role of TET1 in ALD
progression. We will evaluate the impact of TET1 down-regulation on hepatocyte cell death in wild-type (WT)
and TET1 knockout (KO) mice challenged with an alcoholic liquid diet. To further determine the hepatic specific
TET1 role in ALD progression, we will generate liver specific TET1 knockout mice by using albumin promoter
driven Cre mouse and floxed TET1 mouse. The results will significantly advance our knowledge of the
mechanisms by which TET1 modulates hepatocyte cell death and improve our understanding of
pathophysiological mechanisms underlying ALD progression. We also anticipate that it will have a broad
impact on the understanding...

## Key facts

- **NIH application ID:** 10399756
- **Project number:** 7R21AA028576-02
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Chiung-Kuei Huang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $175,727
- **Award type:** 7
- **Project period:** 2021-06-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399756

## Citation

> US National Institutes of Health, RePORTER application 10399756, TET1 in alcoholic liver disease progression (7R21AA028576-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10399756. Licensed CC0.

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