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Arid1a mediates cell recovery upon gastric injury to prevent tumorigenesis [Multiome]

ABSTRACT: When tissues and organs are damaged, they undergo a reversible regenerative response. Since it often activates oncogenic signaling pathways, recovery after regeneration must be precisely regulated. However, its underlying mechanisms and relationship with cancer remain unclear. The stomach is constantly exposed to environmental damages such as H. pylori infection and ulcer, and undergoes an evolutionally conserved, regenerative response called spasmolytic polypeptide-expressing metaplasia (SPEM). Although this process is highly reversible, occurring in precancerous lesions, the epigenetic regulation underlying SPEM is unknown. Our single-cell chromatin and gene expression analysis defines cell fate and state dynamics in homeostasis, regeneration and recovery. Upon injury, gastric epithelial cells rapidly induce SPEM gene expression under accessible chromatin, while losing the expression and accessibility of differentiation genes. Strikingly, when Arid1a, the second most mutated gastric cancer gene, is deleted in regeneration, it abolishes cell recovery. By analyzing histone modification and chromatin accessibility, as well as mapping the binding sites of ARID1A and BRG1, we demonstrate they promote recovery through the regulation of enhancer activity. Notably, failed recovery by Arid1a loss in combination with Trp53 deletion is sufficient to induce cancer initiation and invasion, providing key insight into the mechanistic relationship between tissue recovery after regeneration and cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE269928 | GEO | 2026/06/30

REPOSITORIES: GEO

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ARID1A terminates gastric regeneration to prevent cancer

Project description:Exposed constantly to environmental challenges, the stomach undergoes highly reversible cycles of regeneration and recovery. Although abnormal activation of regeneration is known to be associated with cancer, the mechanisms underlying tissue restoration remain unclear. Our single-cell gene expression and chromatin analysis defined cell state dynamics during regeneration and recovery, identifying the Brahma-related gene 1(BRG1)/BRM-associated factor (BAF) chromatin remodeling complex during recovery. Strikingly, deletion of AT-rich interaction domain 1A (Arid1a), a subunit of the BAF complex and the second most frequently mutated gene in gastric cancer, impaired recovery across multiple murine injury models, resulting in a persistent regenerative state. Integrative analyses combining single-cell multiome and chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that the BAF complex recruits lineage-specific transcription factors such as MIST1 and estrogen related receptor gamma (ERRγ) to regulate enhancers of recovery genes. Notably, deletion of Trp53 in the unresolved regenerative state caused by Arid1a loss is sufficient to drive cancer development and invasion, revealing the epigenetic mechanisms bridging gastric regeneration, recovery, and cancer.

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