# Arsenic disrupts H3K9me3 and H3K27me3 balance by biasing PRC2.1 and PRC2.2 activity via PALI1 inhibition in carcinogenesis

## TL;DR

Arsenic exposure disrupts key chromatin modifications, leading to genome instability and potentially contributing to cancer development.

## Contribution

The study reveals a novel mechanism by which arsenic disrupts histone modifications via PALI1 inhibition, linking it to carcinogenesis.

## Key findings

- Arsenic exposure increases H3K27me3 and decreases H3K9me3 in bronchial epithelial cells.
- Arsenic downregulates PALI1, impairing dual repression of H3K27me3 and H3K9me3.
- Loss of H3K9me3 is associated with genomic instability and activation of cancer-related pathways.

## Abstract

Inorganic arsenic (As3+) is a well-established human carcinogen, yet the molecular mechanisms underlying its oncogenic potential remain incompletely understood. Here, we show that exposure to environmentally relevant concentrations of As³⁺ disrupts chromatin architectures in human bronchial epithelial cells (BEAS-2B) by discordantly regulating two key repressive histone modifications: histone H3 lysine 27 trimethylation (H3K27me3) and H3K9me3. Chromatin immunoprecipitation and sequencing (ChIP-seq) reveals a genome-wide gain of H3K27me3 and a marked loss of H3K9me3 following As³⁺ treatment. Mechanistically, As3+ downregulates PALI1, an essential accessory subunit of the polycomb repressive complex 2.1 (PRC2.1), which uniquely coordinates H3K27me3 and H3K9me3 deposition via EZH2 and G9a, respectively. Loss of PALI1 impairs this dual repression mechanism, leading to widespread chromatin deregulation. Gene ontological analysis reveals that regions with diminished H3K9me3 in As³⁺-treated cells are enriched in pathways related to PRC2 activity, ribosomal biogenesis, stemness-associated transcription factors, xenobiotic metabolism (phases I and II), and GPCR signaling. Notably, these regions also include LINE-1 retrotransposons, whose de-repression is known to drive genomic instability—a hallmark of cancer. Given PALI1's potential tumor-suppressive role in lung, breast, and colon cancers, and other malignancies, its suppression by As³⁺ likely contributes to carcinogenesis through epigenetic reprogramming, genome destabilization, and activation of oncogenic transcriptional programs. These findings reveal a novel mechanism of As³⁺-induced epigenetic dysregulation and highlight the central role of histone modifications in environmental carcinogenesis.