Department of Nutrition and Food Science and Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA; Department of Biology, Texas A&M University, College Station, TX 77843, USA.
Department of Statistics in Texas A&M University, College Station, 77843, TX, USA.
Biochim Biophys Acta Mol Basis Dis. 2017 Jun;1863(6):1392-1402. doi: 10.1016/j.bbadis.2017.03.009. Epub 2017 Mar 16.
During colon cancer, epigenetic alterations contribute to the dysregulation of major cellular functions and signaling pathways. Modifications in chromatin signatures such as H3K4me3 and H3K9ac, which are associated with transcriptionally active genes, can lead to genomic instability and perturb the expression of gene sets associated with oncogenic processes. In order to further elucidate early pre-tumorigenic epigenetic molecular events driving CRC, we integrated diverse, genome-wide, epigenetic inputs (by high throughput sequencing of RNA, H3K4me3, and H3K9ac) and compared differentially expressed transcripts (DE) and enriched regions (DER) in an in-vivo rat colon cancer progression model. Carcinogen (AOM) effects were detected genome-wide at the RNA (116 DE genes), K9ac (49 DERs including 24 genes) and K4me3 (7678 DERs including 3792 genes) level. RNA-seq differential expression and pathway analysis indicated that interferon-associated innate immune responses were impacted by AOM exposure. Despite extensive associations between K4me3 DERs and colon tumorigenesis (1210 genes were linked to colorectal carcinoma) including FOXO3, GNAI2, H2AFX, MSH2, NR3C1, PDCD4 and VEGFA, these changes were not reflected at the RNA gene expression level during early cancer progression. Collectively, our results indicate that carcinogen-induced changes in gene K4me3 DERs are harbingers of future transcriptional events, which drive malignant transformation of the colon.
在结肠癌中，表观遗传改变导致主要细胞功能和信号通路的失调。组蛋白标记如 H3K4me3 和 H3K9ac 的改变与转录活跃的基因相关，可以导致基因组不稳定，并扰乱与致癌过程相关的基因集的表达。为了进一步阐明促进 CRC 的早期肿瘤前表观遗传分子事件，我们整合了多样化的、全基因组的表观遗传输入（通过高通量 RNA、H3K4me3 和 H3K9ac 的测序），并比较了体内大鼠结肠癌进展模型中差异表达的转录物（DE）和富集区域（DER）。致癌物（AOM）的影响在 RNA（116 个 DE 基因）、K9ac（包括 24 个基因的 49 个 DER）和 K4me3（包括 3792 个基因的 7678 个 DER）水平上在全基因组范围内被检测到。RNA-seq 差异表达和通路分析表明，干扰素相关的先天免疫反应受到 AOM 暴露的影响。尽管 K4me3 DER 与结肠癌发生（1210 个基因与结直肠癌相关，包括 FOXO3、GNAI2、H2AFX、MSH2、NR3C1、PDCD4 和 VEGFA）之间存在广泛的关联，但这些变化在早期癌症进展过程中并没有反映在 RNA 基因表达水平上。总之，我们的结果表明，致癌物诱导的 K4me3 DER 基因变化是未来转录事件的先兆，这些事件驱动了结肠的恶性转化。
