# Role of epigenetic crosstalks in directing locus sensitivity to arsenic

> **NIH ES R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2026 · $464,523

## Abstract

PROJECT SUMMARY
 The overarching goal of the research presented in this application is to understand what make some
genomic loci more susceptible than others to environmental chemical perturbation. Using inorganic arsenic
(iAs) as a model environmental toxicant of high human relevance, we will seek to mechanistically investigate
how epigenetic crosstalks dictate locus-specific sensitivity to arsenic.
 iAs is a model epigenetic toxicant owing to its well described impact on global DNA hypomethylation
coinciding with a reduction in the levels of the universal methyl donor SAM, used towards DNA and histone
methylation. However, this model of epigenetic mechanism of iAs has been acknowledged as largely
unsatisfactory since (1) even in the context of global DNA hypomethylation, some loci show hypermethylation
while others show no change, and (2) the effect on histone methylation are non-uniform with many methylated
histone marks showing increases while others show a decrease. Here, we propose to build on compelling
preliminary data obtained through highly quantitative Mass Spec and metabolomic studies that show that in
mouse ESCs, at levels where sodium arsenite does not cause a significant increase in ROS levels, a
pronounced decrease in SAM, DNA methylation, and in several histone marks, such as H3K36me2/3, are
observed. However, H3K27me3 levels are increased while H3K9me3 levels are unchanged. Furthermore,
RNA-seq studies revealed even in the context of profound transcriptional changes, repetitive elements that are
repressed by deposition of H3K9me3 remain transcriptionally silenced following sodium arsenite exposure.
Thus, we hypothesize that epigenetic crosstalks can differentially compete for the reduced SAM pool
caused by iAs exposure, thereby driving locus sensitivity.
 To test this hypothesis, we will use mouse ESCs where crosstalks are well characterized. In aim 1, we will
characterize the genome-wide changes in DNA methylation and in 3 distinct histone PTMs. W

## Key facts

- **NIH application ID:** 11222686
- **Project number:** 5R01ES034251-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Patrick  Allard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** ES
- **Fiscal year:** 2026
- **Award amount:** $464,523
- **Award type:** 5
- **Project period:** 2023-01-25T00:00:00 → 2027-10-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11222686

## Citation

> US National Institutes of Health, RePORTER application 11222686, Role of epigenetic crosstalks in directing locus sensitivity to arsenic (5R01ES034251-04). Retrieved via AI Analytics 2026-05-18 from https://api.ai-analytics.org/grant/nih/11222686. Licensed CC0.

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