Department of Nutrition and Food Science - Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX.
Department of Biology, Texas A&M University, College Station, TX.
Int J Cancer. 2018 Sep 15;143(6):1402-1415. doi: 10.1002/ijc.31525. Epub 2018 May 10.
Dietary fermentable fiber generates short-chain fatty acids (SCFA), for example, butyrate, in the colonic lumen which serves as a chemoprotective histone deacetylase inhibitor and/or as an acetylation substrate for histone acetylases. In addition, n-3 polyunsaturated fatty acids (n-3 PUFA) in fish oil can affect the chromatin landscape by acting as ligands for tumor suppressive nuclear receptors. In an effort to gain insight into the global dimension of post-translational modification of histones (including H3K4me3 and H3K9ac) and clarify the chemoprotective impact of dietary bioactive compounds on transcriptional control in a preclinical model of colon cancer, 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 diets containing bioactive (i) fish oil, (ii) fermentable fiber (a rich source of SCFA), (iii) a combination of fish oil plus pectin, or (iv) control, devoid of fish oil or pectin. In general, poor correlation was observed between differentially transcribed (DE) and enriched genes (DERs) at multiple epigenetic levels. The combinatorial diet (fish oil + pectin) uniquely affected transcriptional profiles in the intestinal epithelium, for example, upregulating lipid catabolism and beta-oxidation associated genes. These genes were linked to activated ligand-dependent nuclear receptors associated with n-3 PUFA and were also correlated with the mitochondrial L-carnitine shuttle and the inhibition of lipogenesis. These findings demonstrate that the chemoprotective fish oil + pectin combination diet uniquely induces global histone state modifications linked to the expression of chemoprotective genes.
膳食纤维在结肠腔中产生短链脂肪酸（SCFA），例如丁酸盐，作为化学保护组蛋白去乙酰化酶抑制剂和/或组蛋白乙酰转移酶的乙酰化底物。此外，鱼油中的 n-3 多不饱和脂肪酸（n-3 PUFA）可以通过作为肿瘤抑制核受体的配体来影响染色质景观。为了深入了解组蛋白（包括 H3K4me3 和 H3K9ac）的翻译后修饰的全局维度，并阐明膳食生物活性化合物对结肠癌临床前模型中转录控制的化学保护作用，我们生成了高分辨率全基因组 RNA（RNA-Seq）和“染色质状态”（H3K4me3-seq 和 H3K9ac-seq）图谱用于用结肠致癌物处理的大鼠的肠（上皮结肠细胞）隐窝，并喂食含有生物活性的（i）鱼油，（ii）可发酵纤维（SCFA 的丰富来源），（iii）鱼油加果胶的组合或（iv）不含鱼油或果胶的对照饮食。一般来说，在多个表观遗传水平上，差异转录（DE）和富集基因（DERs）之间观察到相关性差。组合饮食（鱼油+果胶）独特地影响肠上皮的转录谱，例如上调与脂质代谢和β-氧化相关的基因。这些基因与与 n-3 PUFA 相关的激活配体依赖性核受体有关，并且还与线粒体 L-肉碱穿梭和脂肪生成抑制相关。这些发现表明，化学保护鱼油+果胶组合饮食独特地诱导与化学保护基因表达相关的全局组蛋白状态修饰。
