# Nuclear moonlighting of arsenic metabolic enzymes and reprogramming-resistant epimutations

> **NIH ES R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2026 · $605,062

## Abstract

PROJECT SUMMARY
 The overarching goal of the research presented in this application is to understand how environmental
chemicals trigger a deregulation of the epigenome that can resist epigenetic reprogramming in germ cells and
therefore can become heritable.
 Inorganic 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. iAs is also a chemical with well-established transgenerational epigenetic inheritance
effects, producing heritable reproductive and metabolic dysfunctions and neurobehavioral outcomes for multiple
generations. However, iAs shows remarkable complexity in its epigenetic impact since even in the context of
global DNA hypomethylation, some loci show hypermethylation and the effect on histone methylation are non-
uniform with many methylated histone marks showing increases while others show a decrease. It is unclear how
iAs causes such varied epigenetic effect and how these effects are maintained during reprogramming.
 Here, we propose to leverage a unique model of germ cell reprogramming based on the step-wise
differentiation of mouse Embryonic Stem Cells (ESCs) into Primordial Germ Cell-Like Cells (PGCLCs). PGCLCs
undergo epigenetic reprogramming in vitro and are transcriptionally and functionally similar to in vivo PGCs since
they generate viable offspring upon transplantation in vivo. We will build on compelling preliminary data showing
that in mESCs, at levels where sodium arsenite does not cause a significant increase in ROS levels, a
pronounced metabolic impact on the methionine cycle and on the transsulfuration pathways are observed
concomitant with its epigenetic impact. We also show that two enzymes crucial for the one-carbon and iAs
metabolism, MAT2A and AS3MT, respectively, are strongly upregulated in response to iAs and translocate to
the nucleus where they associate 

## Key facts

- **NIH application ID:** 11262947
- **Project number:** 5R01ES036923-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Patrick  Allard; Qi  Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** ES
- **Fiscal year:** 2026
- **Award amount:** $605,062
- **Award type:** 5
- **Project period:** 2025-01-23T00:00:00 → 2029-11-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11262947

## Citation

> US National Institutes of Health, RePORTER application 11262947, Nuclear moonlighting of arsenic metabolic enzymes and reprogramming-resistant epimutations (5R01ES036923-02). Retrieved via AI Analytics 2026-07-06 from https://api.ai-analytics.org/grant/nih/11262947. Licensed CC0.

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