Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression

High-fat diet and obesity are high risk factors for colorectal cancer. The underlying mechanism is still unclear. Environmental factors alter the epigenome to affect gene expression thus the phenotype. In response to external stimuli, the cis-regulatory regions, especially enhancer loci, are key elements for regulating selective gene expression. We thus explored the effects of high-fat diet and the accompanying obesity on gene expression and the enhancer landscape in colon epithelium. High-fat diet exposed binding sites of transcription factors downstream of signaling pathways important in the initiation and progression of colon cancer. Meantime, colon specific enhancers were lost rendering the cells potential for dedifferentiation. The alteration at enhancer regions drives a specific transcription program promoting colon cancer progression. The comprehensive interrogation of enhancer changes by high-fat diet in colon epithelium provides a number of insights into the underlying biology of high-fat diet and obesity in increasing colon cancer risk, and provides potential therapeutic targets to treat obese colon cancer patients. ChIP sequencing of active enhancer mark h3k27ac in colon epithelium from wild type mice and NAG-1 transgenic mice treated with either low-fat diet or high-fat diet. The gene expression component of the study is included in GSE46843.

高脂饮食与肥胖是结直肠癌的高危风险因素，但其潜在分子机制仍未阐明。环境因素可通过改变表观基因组调控基因表达，进而影响细胞表型。在外界刺激下，顺式调控区域（尤其是增强子位点）是调控选择性基因表达的核心元件。因此，本研究探讨了高脂饮食伴随肥胖对结肠上皮细胞基因表达及增强子图谱的影响。研究发现，高脂饮食可使结直肠癌发生与进展相关信号通路下游的转录因子结合位点得以暴露；与此同时，结肠特异性增强子发生丢失，使细胞获得去分化潜能。增强子区域的表观遗传改变驱动了一套特异性转录程序，进而促进结直肠癌的进展。本研究通过全面解析高脂饮食诱导的结肠上皮增强子变化，为阐明高脂饮食与肥胖升高结直肠癌风险的潜在生物学机制提供了多项新见解，同时也为肥胖相关结直肠癌患者的治疗提供了潜在治疗靶点。本研究对分别经低脂饮食或高脂饮食处理的野生型小鼠及NAG-1转基因小鼠的结肠上皮细胞中的活跃增强子标记H3K27ac进行了染色质免疫共沉淀测序（ChIP sequencing）。本研究的基因表达组数据已收录于GSE46843数据集。