背景:增强子转录失调发生在多种癌症中。增强子RNA(eRNA)是来自增强子的转录产物,其在转录控制中起关键作用。表征eRNA表达的遗传基础可以阐明癌症的分子机制。
方法:最初,在癌症基因组图谱(TCGA)中对eRNA定量性状基因座(eRNAQTLs)进行了全面分析,和功能特征使用多组学数据进行表征。建立国内首个结直肠癌(CRC)的eNAQTL图谱,表观基因组数据用于定义活性增强剂,随后与154个配对CRC样本的转录和基因分型数据整合。最后,我们进行了大规模病例对照研究(34,585例病例和69,544例对照)以及多管齐下的实验,以研究候选eRNAQTL影响CRC风险的潜在机制.
结果:在30种不同的癌症类型中,共鉴定出300,112个eRNAQTL,它们通过调节染色质状态对eRNA转录产生影响,与转录因子和RNA结合蛋白的结合亲和力。这些eRNAQTL被发现在癌症风险基因座中显著富集,解释了相当大比例的癌症遗传力。此外,肿瘤特异性eRNAQTLs对癌症的发展表现出很高的反应性.此外,这些eRNAs的靶基因与癌症中信号通路失调和免疫细胞浸润有关,突出它们作为治疗靶点的潜力。此外,多种族人群研究证实,eRNAQTLrs3094296-T变异可降低中国(OR=0.91,95CI0.88-0.95,P=2.92×10-7)和欧洲(OR=0.92,95CI0.88-0.95,P=4.61×10-6)人群的CRC风险.机械上,rs3094296对ENSR00000155786eRNA的转录具有等位基因特异性作用,该eRNA充当促进其靶基因SENP7表达的转录激活因子。这两个基因协同抑制肿瘤细胞增殖。我们精选的变体列表,基因,和药物已在CancereRNAQTL(http://canernaqtl.whu.edu.cn/#/)作为推进这一领域的信息资源。
结论:我们的发现强调了eNAQTLs在转录调控和疾病遗传力方面的重要性,指出了基于eRNA的癌症治疗策略的潜力。
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 dysregulated signaling pathways and immune cell infiltration in cancer, highlighting their potential as therapeutic targets. Furthermore, multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from
China (OR = 0.91, 95%CI 0.88-0.95, P = 2.92 × 10-7) and Europe (OR = 0.92, 95%CI 0.88-0.95, P = 4.61 × 10-6). Mechanistically, rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786, which functioned as a transcriptional activator promoting the expression of its target gene SENP7. These two genes synergistically suppressed tumor cell proliferation. Our curated list of variants, genes, and drugs has been made available in CancereRNAQTL ( http://canernaqtl.whu.edu.cn/#/ ) to serve as an informative resource for advancing this field.
CONCLUSIONS: Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.