Assessment of Histone Tail Modifications and Transcriptional Profiling During Colon Cancer and Role of fish oil/pectin Diet Against Colon Carcinogen

In an effort to gain insight into the extensive dimension of post-translational modifications in histones (including H3K4me3 and H3K9ac) and elucidate the chemoprotective impact of dietary bioactive compounds on transcriptional control in a colon cancer preclinical model, we generated high-resolution genome-wide RNA (RNA-Seq) and “chromatin-state” (H3K4me3-seq and H3K9ac-seq) maps for intestinal (epithelial colonocytes) crypts in rats treated with a colon carcinogen and fed bioactive (i) fish oil (ii) butyrate (in the form of a fermentable fiber a rich source of SCFA), (iii) a combination of fish oil plus butyrate or (iv) control diets. Poor correlation was observed between differentially transcribed (DE) and enriched genes (DERs) at multiple epigenetic levels in fat x fiber dietary combinations and in the presence/absence of carcinogen. We also demonstrated that the combinatorial diet (fish oil + pectin) was synergistically chemoprotective, and uniquely affected epigenetic profiles in the intestinal epithelium, e.g., upregulating lipid catabolism and beta-oxidation associated genes.为深入解析组蛋白（包括H3K4me3与H3K9ac）广泛存在的翻译后修饰特征，并阐明膳食生物活性成分对结肠癌临床前模型中转录调控的化学保护作用，我们对经结肠致癌物处理、并分别饲喂四类膳食的大鼠肠道（上皮结肠细胞）隐窝，构建了高分辨率全基因组RNA测序（RNA-Seq）及染色质状态（H3K4me3-seq与H3K9ac-seq）图谱。四类膳食分别为：(i) 鱼油膳食；(ii) 丁酸膳食（以可发酵膳食纤维形式供给，为短链脂肪酸（Short-Chain Fatty Acid, SCFA）的丰富来源）；(iii) 鱼油与丁酸联合膳食；(iv) 对照膳食。在脂肪-膳食纤维膳食组合及存在/不存在致癌物的实验条件下，多个表观遗传层面的差异转录（Differentially Transcribed, DE）基因与富集基因（DERs）之间相关性较弱。本研究同时证实，鱼油+果胶联合膳食具有协同化学预防效应，并可特异性调控肠道上皮的表观遗传谱，例如上调脂质分解代谢与β-氧化相关基因。