# Chromatin assembly and formaldehyde toxicity

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $541,277

## Abstract

PROJECT SUMMARY
Formaldehyde is a known environmental and occupational chemical carcinogen. The molecular mechanisms of
formaldehyde-induced carcinogenesis are largely undetermined. The DNA damage and associated
mutagenesis induced by DNA adducts and DNA-protein crosslinks have been the focus of formaldehyde
carcinogenicity research. However, recent studies showed that exogenous formaldehyde caused only a
modest increase in DNA adducts above levels caused by endogenous formaldehyde. This suggested the
possibility that epigenetic mechanisms might contribute to formaldehyde-induced carcinogenicity. We and
others have demonstrated that formaldehyde reacts with lysine residues on histone proteins to form a labile
Schiff base or the more stable N6-formyllysine, and that both Schiff bases and N6-formyllysine residues are
refractory to acetylation. These findings indicated that formaldehyde-histone lysine adducts might interfere with
important cellular process regulated by histone lysine acetylation. However, it remains unknown which process
is affected by this mechanism. Our preliminary data from cellular fractionation analyses demonstrate that
formaldehyde exposure dramatically decreases lysine acetylations of the cytosolic histones H3 and H4. This
finding is very intriguing, given that these modifications are critical for histone nuclear import and chromatin
assembly. Our preliminary results further show that formaldehyde reduces the total amount of histone in the
chromatin fraction and the levels of histones at genomic loci, suggesting inhibition of chromatin assembly.
Defective chromatin assembly causes dysregulation of gene expression and genomic instability and was
directly linked to different types of cancers. Based on these observations, we hypothesize that the formation of
formaldehyde-histone adducts compromises histone nuclear import and/or chromatin assembly, thereby
contributing to formaldehyde-induced carcinogenesis. To test this hypothesis, in Aim 1, we will examine
whether the nuclear import of newly synthesized histones and their assembly into chromatin are compromised
following formaldehyde exposure and determine the underlying mechanisms. In Aim 2, we will determine the
impact of aberrant chromatin assembly on formaldehyde-induced changes in gene expression, formation of
DNA adducts and DNA-protein crosslinks, and chromosome instability. In Aim 3, we will investigate whether
formaldehyde exposure compromises chromatin assembly in vivo. The proposed concept that a chemical
carcinogen reacts with newly synthesized histones to regulate chromatin assembly is novel. This study has the
potential to reveal a new mechanism for chemical carcinogenesis.

## Key facts

- **NIH application ID:** 10758626
- **Project number:** 5R01ES033160-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Chunyuan Jin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $541,277
- **Award type:** 5
- **Project period:** 2022-03-25 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10758626

## Citation

> US National Institutes of Health, RePORTER application 10758626, Chromatin assembly and formaldehyde toxicity (5R01ES033160-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10758626. Licensed CC0.

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