# Molecular mechanisms of iAs-mediated carcinogenesis through the lens of histone H2B variants

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2022 · $612,330

## Abstract

Establishing the influence of pollutants on genome function is essential in defining their impact on
human health. Arsenic is a ubiquitous environmental toxic metalloid that leads to carcinogenesis. The World
Health Organization estimates that over 100 million people worldwide are at risk to drinking arsenic
contaminated water. Recent studies indicate that arsenic alters gene expression leading to tumorigenesis.
Proper gene regulation is essential for normal growth, development and etiology of diseases such as cancer.
Eukaryotic DNA stored as chromatin whose basic repeating unit is the nucleosome, plays an integral role in
gene regulation. Previously, we (and others) showed that nucleosome locations within promoters play critical
roles in chromatin accessibility, thus controlling gene activity. Consequently, chromatin accessibility is an
essential component in gene regulation yet is not fully understood. Chromatin accessibility is modulated by
several key epigenetic factors: histone post-translational modifications (PTMs), DNA methylation, nucleosome
position/occupancy, transcription factors and chromatin architectural proteins (CAPs). We showed recently that
in addition to the above, incorporation of histone variants (the elusive H2B), into chromatin play a significant
role in arsenic-mediated diseases pathology, yet a mechanistic understanding of their impact is unknown.
These histone variants differ by just one to maximally three amino acids from the canonical H2B histone and
are highly expressed in cancers, suggesting that they could act as `oncohistones'. Thus it is critically important
to understand how and why these histone variants get expressed (aim 1); how their chromatin integration
impacts chromatin structural dynamics (aim 2) and integration regulate the chromatin state and gene
expression during arsenic exposure to drive carcinogenesis (aim3). Our interdisciplinary, broad approach will
establish unique comprehensive functional and mechanistic insight into histone H2B variant expression,
chromatin integration and disease pathology. Further it will provide a detailed understanding of the interplay
between arsenic-induced epigenetic changes and chromatin in the mammalian cell. We have developed novel
systems that will provide an unprecedented and unique opportunity to discover the functional and mechanistic
roles of the epigenome in toxicant-induced diseases.

## Key facts

- **NIH application ID:** 10465422
- **Project number:** 1R01ES034253-01
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Yvonne Nsokika Fondufe-Mittendorf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $612,330
- **Award type:** 1
- **Project period:** 2022-05-02 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465422

## Citation

> US National Institutes of Health, RePORTER application 10465422, Molecular mechanisms of iAs-mediated carcinogenesis through the lens of histone H2B variants (1R01ES034253-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10465422. Licensed CC0.

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