ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice [primary cells_ChIP-seq]

Genes encoding subunits of SWI/SNF chromatin remodeling complexes are collectively mutated in ~20% of all human cancers. Although ARID1A is the most frequent target of mutations, the mechanism by which its inactivation promotes tumorigenesis is unclear. Here, we demonstrate that Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine, and that invasive ARID1A-deficient adenocarcinomas resemble human colorectal cancer (CRC). These tumors lack deregulation of APC/beta-catenin, crucial gatekeepers in common forms of intestinal cancer. ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors (TFs) to facilitate gene activation. ARID1B preserves SWI/SNF function in ARID1A-deficient cells, but defects in SWI/SNF targeting and control of enhancer activity cause extensive dysregulation of gene expression. These findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as a principal tumor suppressor function of ARID1A. ChIP-seq for H3K27ac and H3K4me3 in Primary Colon Epithelial cells form WT and ARID1A-KO mice.

SWI/SNF染色质重塑复合物（SWI/SNF chromatin remodeling complexes）亚基的编码基因，在约20%的人类癌症中发生突变。尽管ARID1A是最常见的突变靶点，但其失活促进肿瘤发生的具体机制仍不明确。本研究证实，Arid1a在小鼠结肠中发挥肿瘤抑制因子（tumor suppressor）功能，而非小肠；且ARID1A缺陷型侵袭性腺癌与人结直肠癌（colorectal cancer, CRC）表型高度相似。此类肿瘤不存在APC/β-连环蛋白（APC/beta-catenin）的失调，而APC/β-连环蛋白是常见肠道癌症的关键抑癌守门因子。ARID1A通常可将SWI/SNF复合物靶向招募至增强子区域，在此处与转录因子（transcription factors, TFs）协同作用以介导基因激活。在ARID1A缺陷的细胞中，ARID1B可维持SWI/SNF复合物的功能，但SWI/SNF靶向缺陷及增强子活性调控异常会引发基因表达的广泛失调。本研究在结肠癌建模领域取得重要进展，并证实增强子介导的基因调控是ARID1A核心的肿瘤抑制功能机制。本数据集包含野生型（WT）与ARID1A敲除（ARID1A-KO）小鼠原代结肠上皮细胞中H3K27ac与H3K4me3的染色质免疫共沉淀测序（ChIP-seq, Chromatin Immunoprecipitation sequencing）数据。