Genome-wide enhancer RNA profiling adds molecular links between genetic variation and human cancers

作者：Yimin Cai, Ze-Qun Lu, Bin Li, Jinyu Huang, Ming Zhang, Can Chen, Lin-Yun Fan, Qianying Ma, Chun-Yi He, Shuoni Chen, Yuan Jiang, Yanmin Li, Caibo Ning, Fuwei Zhang, Wenzhuo Wang, Yi-Zhuo Liu, Heng Zhang, Meng Jin, Xiaoyang Wang, Jin-Xin Han, Zhen Xiong, Ming Cai, Chao-Qun Huang, Xiaojun Yang, Xu Zhu, Ying Zhu, Xiaoping Miao, Shao-Kai Zhang, Yongchang Wei, Jianbo Tian · 发表于：Military Medical Research · 年份：2024 · DOI：10.1186/s40779-024-00539-2 · 被引用次数：9 · 研究领域：Genomics and Chromatin Dynamics、Epigenetics and DNA Methylation、Chromatin Remodeling and Cancer

Abstract Background Dysregulation of enhancer transcription occurs in multiple cancers. Enhancer RNAs (eRNAs) are transcribed products from enhancers that play critical roles in transcriptional control. Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers. Methods Initially, a comprehensive analysis of eRNA quantitative trait loci (eRNAQTLs) was performed in The Cancer Genome Atlas (TCGA), and functional features were characterized using multi-omics data. To establish the first eRNAQTL profiles for colorectal cancer (CRC) in China, epigenomic data were used to define active enhancers, which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples. Finally, large-scale case-control studies (34,585 cases and 69,544 controls) were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk. Results A total of 300,112 eRNAQTLs were identified across 30 different cancer types, which exert their influence on eRNA transcription by modulating chromatin status, binding affinity to transcription factors and RNA-binding proteins. These eRNAQTLs were found to be significantly enriched in cancer risk loci, explaining a substantial proportion of cancer heritability. Additionally, tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer. Moreover, the target genes of these eRNAs were associated with dy...