全基因组增强子 RNA 分析增加了基因变异与人类癌症之间的分子联系。

IF 16.7 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Military Medical Research Pub Date : 2024-06-11 DOI:10.1186/s40779-024-00539-2
Yi-Min Cai, Ze-Qun Lu, Bin Li, Jin-Yu Huang, Ming Zhang, Can Chen, Lin-Yun Fan, Qian-Ying Ma, Chun-Yi He, Shuo-Ni Chen, Yuan Jiang, Yan-Min Li, Cai-Bo Ning, Fu-Wei Zhang, Wen-Zhuo Wang, Yi-Zhuo Liu, Heng Zhang, Meng Jin, Xiao-Yang Wang, Jin-Xin Han, Zhen Xiong, Ming Cai, Chao-Qun Huang, Xiao-Jun Yang, Xu Zhu, Ying Zhu, Xiao-Ping Miao, Shao-Kai Zhang, Yong-Chang Wei, Jian-Bo Tian
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引用次数: 0

摘要

背景:增强子转录失调发生在多种癌症中。增强子 RNA(eRNA)是增强子的转录产物,在转录控制中发挥着关键作用。表征 eRNA 表达的遗传基础可阐明癌症的分子机制:最初,在癌症基因组图谱(TCGA)中对eRNA定量性状位点(eRNAQTLs)进行了全面分析,并利用多组学数据对其功能特征进行了表征。为了建立中国首个结直肠癌(CRC)eRNAQTL图谱,研究人员利用表观基因组学数据定义了活跃的增强子,随后将这些增强子与来自154个配对CRC样本的转录和基因分型数据进行了整合。最后,进行了大规模的病例对照研究(34585例病例和69544例对照),并通过多管齐下的实验研究候选eRNAQTLs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、与转录因子和RNA结合蛋白的结合亲和力,对eRNA转录产生影响。研究发现,这些 eRNAQTLs 显著富集于癌症风险位点,可解释癌症遗传性的很大一部分。此外,肿瘤特异性 eRNAQTL 对癌症的发生表现出高度的反应性。此外,这些 eRNA 的靶基因与癌症中失调的信号通路和免疫细胞浸润有关,突出了它们作为治疗靶点的潜力。此外,多项种族人群研究证实,在中国(OR = 0.91,95%CI 0.88-0.95,P = 2.92 × 10-7)和欧洲(OR = 0.92,95%CI 0.88-0.95,P = 4.61 × 10-6)人群中,eRNAQTL rs3094296-T 变体可降低患 CRC 的风险。从机制上看,rs3094296 对 eRNA ENSR00000155786 的转录具有等位基因特异性影响,而 eRNA ENSR00000155786 是一种转录激活剂,可促进其靶基因 SENP7 的表达。这两个基因协同抑制了肿瘤细胞的增殖。我们策划的变体、基因和药物列表已在 CancereRNAQTL ( http://canernaqtl.whu.edu.cn/#/ ) 中公布,成为推动这一领域发展的信息资源:我们的研究结果强调了 eRNAQTL 在转录调控和疾病遗传性方面的重要性,并指出了基于 eRNA 的癌症治疗策略的潜力。
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Genome-wide enhancer RNA profiling adds molecular links between genetic variation and human cancers.

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.

Conclusion: Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.

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来源期刊
Military Medical Research
Military Medical Research Medicine-General Medicine
CiteScore
38.40
自引率
2.80%
发文量
485
审稿时长
8 weeks
期刊介绍: Military Medical Research is an open-access, peer-reviewed journal that aims to share the most up-to-date evidence and innovative discoveries in a wide range of fields, including basic and clinical sciences, translational research, precision medicine, emerging interdisciplinary subjects, and advanced technologies. Our primary focus is on modern military medicine; however, we also encourage submissions from other related areas. This includes, but is not limited to, basic medical research with the potential for translation into practice, as well as clinical research that could impact medical care both in times of warfare and during peacetime military operations.
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