# Smoking-Induced Epigenetic Changes in the Lung: Role of DNA Demethylation

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $358,171

## Abstract

Abstract
Cytosine methylation (5-methylcytosine (MeC)) regulates gene expression in a tissue-specific manner. These
methylation marks are introduced by DNA methyltransferases (DNMTs), which catalyze de novo methylation of
CpG sites and maintain DNA methylation patterns to allow for activation and silencing of specific genes. Ten
eleven translocation proteins (Tet) catalyze α-ketoglutarate-dependent oxidation of MeC to 5-hydroxymethyl-
cytosine (hmC), 5-formylcytosine (fC), and 5-carboxylcytosine (caC). These oxidized forms of MeC serve as
demethylation intermediates, leading to gene reactivation. Furthermore, studies in the brain and embryonic
stem cells have shown that hmC, fC, and caC can be recognized by specific protein readers and may have
epigenetic functions of their own. Cytosine methylation patterns are stable in normal somatic tissues, but are
significantly altered in many diseases including cancer, asthma, and autism. Specifically, scrambled DNA
methylation and hydroxymethylation in cancer leads to silencing of tumor suppressor genes and activation of
protooncogenes. We have shown that chronic inflammation and exposure to tobacco nitrosamines induces
early epigenetic changes in the A/J model of lung cancer. These alterations are detectable long before the
formation of tumors and include changes in cytosine methylation, hydroxymethylation, formylation, and histone
acetylation. However, the functional outcomes of these epigenetic changes remain to be determined. This
research plan focuses on investigating the functions of MeC, hmC, fC, and caC in the lung, characterizing
epigenetic changes associated with smoking and inflammation, and elucidating the epigenetic functions of Tet
proteins in the lung. Taken together, these studies will contribute to our understanding of normal epigenetic
mechanisms in the lung and their response to smoking and inflammation.

## Key facts

- **NIH application ID:** 10064607
- **Project number:** 5R01CA095039-13
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** NATALIA Y TRETYAKOVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,171
- **Award type:** 5
- **Project period:** 2002-12-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064607

## Citation

> US National Institutes of Health, RePORTER application 10064607, Smoking-Induced Epigenetic Changes in the Lung: Role of DNA Demethylation (5R01CA095039-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10064607. Licensed CC0.

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