Poster Session I - Poster of Distinction I - A18 EXPLORING THE REGULATORY ROLE OF ARID1A IN ADULT COLONIC HOMEOSTASIS AND INJURY RESPONSE

TL;DR

This study explores how ARID1A affects colon recovery and cancer risk after injury, showing its role in tissue repair and tumor development.

Contribution

The study reveals ARID1A's role in colonic injury recovery and its link to tumor formation through Wnt pathway regulation and goblet cell differentiation.

Findings

Arid1a deletion causes delayed recovery from colitis and leads to tumor-like structures over time.

Arid1a influences goblet cell differentiation and Wnt pathway activity during tissue regeneration.

Loss of Arid1a results in reduced stem and goblet cells and dysregulated KLF4 expression.

Abstract

Recent advances in cancer genome analysis have illustrated the role of epigenetic regulators in cancer development. One regulator, ARID1A (AT-rich interactive domain containing protein 1A), a key component of the BAF (BRG1/BRM associated factor) chromatin remodeling complex, is frequently mutated in colorectal cancer (CRC), the third most prevalent cancer worldwide. Moreover, whole genome sequencing analysis has shown that ARID1A is highly altered in IBD patients along with other CRC-associated genes, such as TP53 and APC. In fact, colonic injury resulting from conditions such as inflammatory bowel disease (IBD) is a significant risk factor for colorectal cancer, also known as colitis-associated cancer (CAC). Additionally, ARID1A is important for intestinal stem cell function during development, but its loss in epithelial and stromal tissue leads to colonic adenoma in adult mice. Therefore, the exact role of ARID1A in the adult colonic epithelia remains unclear.

To comprehensively address the role of ARID1A in the adult colon, I aim to: 1. Determine the role of  Arid1a  during colonic homeostasis and injury. 2. Elucidate the regulatory mechanism by  Arid1a  during colitis.

Tissue-specific Arid1a conditional KO mouse (Villin-CreERT2; Arid1afl/fl) was used for histological analysis after Arid1a KO. Additionally, after administering dextran sulfate sodium (DSS) to induce colitis-like injuries in the mouse colon, Arid1a was deleted during tissue regeneration and examined after short- and long-term.

While Arid1a deletion did not cause morphological differences in adult mice colon, Arid1a-deficient colons with DSS-induced colitis showed delayed recovery (Fig1A-F). Long-term Arid1a- colitis tissues showed visible tumor-like structures characterized by high-grade dysplasia, a hallmark event in CAC development (Fig1G-H). Single cell RNA- and ATAC-seq analyses revealed reduced stem- and goblet cells and downregulated motif enrichment of goblet cell lineage regulator, KLF4, in Arid1a- tissues, consistent with short-term goblet cell differentiation defect and stem cell number decrease in vivo (Fig1 I-M). Additionally, ARID1A and enhancer-specific ChIP-seq on recovered tissue revealed enrichment in β-catenin binding, suggesting Arid1a regulation of Wnt pathway activity during recovery. Indeed, long-term Arid1a- dysplastic tissues show higher nuclear β-catenin localization, suggesting overactivation of Wnt pathway in the absence of Arid1a (Fig1 N-P).

1. Arid1a is important for colonic injury recovery, and its loss results in short-term recovery defects and long-term tumorigenesis. 2. Arid1a may interact with KLF4 to regulate goblet cell differentiation and regulate Wnt pathway activation during injury recovery.

CIHR

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