Genome-wide analysis of enhancer landscape in colorectal cancer subgroups (RNA-seq)

Colorectal cancer (CRC) is a highly malignant solid tumor and causes millions of cancer related death worldwide. Here, using H3K27ac chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with gene expression data (RNA-seq), we describe the active cis-regulatory landscape across more than seventy diverse CRC patient tissues, including tumor and native tissue. Analysis of the enhancers and super-enhancers with recurrently gained or lost activity revealed novel, clinically relevant insights into CRC biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors which is responsible for tumorigenesis and the maintenance of normal intestinal function. Genomic studies have revealed four distinct consensus molecular subgroups (CMS) with divergent biology and clinical behavior and we reveal that differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity. Our integrated analysis of enhancer elements in a large series of CRC patient paired samples reveals novel insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins. mRNA profiles of tumor and native tissue from 72 CRC patients were generated by RNA-seq, using Illumina NovaSeq.

结直肠癌（Colorectal cancer, CRC）是一类高恶性实体瘤，在全球范围内导致数百万例癌症相关死亡。本研究通过结合组蛋白H3赖氨酸27乙酰化（H3K27ac）染色质免疫共沉淀测序（ChIP-seq）与基因表达数据（RNA测序，RNA-seq），构建了覆盖70余例不同结直肠癌患者组织的活性顺式调控景观，样本涵盖肿瘤组织与正常配对组织。对活性反复获得或缺失的增强子与超级增强子进行分析，为结直肠癌的生物学特性提供了全新且具有临床相关性的认知。通过核心调控环路的计算重构，本研究鉴定出一组主控转录因子，其参与肿瘤发生过程并维持正常肠道功能。基因组学研究已揭示四类具有迥异生物学特性与临床行为的共识分子亚型（Consensus Molecular Subgroups, CMS），本研究发现差异调控的增强子与超级增强子进一步强化了各亚型间的异质性。本研究对大规模结直肠癌患者配对样本中的增强子元件开展整合分析，为顺式调控架构、未被认知的调控依赖关系以及细胞起源提供了全新认知。本研究通过Illumina NovaSeq平台，对72例结直肠癌患者的肿瘤组织与正常配对组织进行RNA测序，获取了对应的mRNA表达谱。