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ゲノム全体のエンハンサーRNAプロファイリングは遺伝的変異とヒトがんとの分子レベルの関連を追加します

  • role： Contribute equally, First author同等贡献者, 第一作者
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

    Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China

    Department of Cancer Epidemiology, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China

Yi-Min Cai123,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

    Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China

    Department of Cancer Epidemiology, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China

Ze-Qun Lu123,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

    Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China

    Department of Cancer Epidemiology, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China

Bin Li123,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Jin-Yu Huang1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Ming Zhang1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Can Chen1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Lin-Yun Fan1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Qian-Ying Ma1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Chun-Yi He1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Shuo-Ni Chen1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Yuan Jiang1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Yan-Min Li1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Cai-Bo Ning1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Fu-Wei Zhang1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Wen-Zhuo Wang1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Yi-Zhuo Liu1,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Heng Zhang1,  
  • Affiliation：

    Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

Meng Jin4,  
  • Affiliation：

    Department of Cancer Epidemiology, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China

Xiao-Yang Wang3,  
  • Affiliation：

    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

Jin-Xin Han5,  
  • Affiliation：

    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

Zhen Xiong5,  
  • Affiliation：

    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

Ming Cai5,  
  • Affiliation：

    Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China

Chao-Qun Huang6,  
  • Affiliation：

    Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China

Xiao-Jun Yang6,  
  • Affiliation：

    Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China

Xu Zhu7,  
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

Ying Zhu1,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

    Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China

    Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

    Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China

  • Email：xpmiao@whu.edu.cn
  • Introduction：*xpmiao@whu.edu.cn;
Xiao-Ping Miao1289*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Cancer Epidemiology, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China

  • Email：shaokaizhang@126.com
  • Introduction：shaokaizhang@126.com;
Shao-Kai Zhang3*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Gastrointestinal Oncology, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

  • Email：weiyongchang@whu.edu.cn
  • Introduction：weiyongchang@whu.edu.cn;
Yong-Chang Wei10*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, Tai-Kang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China

    Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China

    Department of Cancer Epidemiology, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China

  • Email：tianjb@whu.edu.cn
  • Introduction：tianjb@whu.edu.cn
Jian-Bo Tian123*

サマリー

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, largescale 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.

キーワード

Enhancer RNA (eRNA);eRNA quantitative trait loci (eRNAQTLs);Genome-wide association study (GWAS);ENSR00000155786;SENP7

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