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

Autor: Cai YM; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang 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., Lu ZQ; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang 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., Li B; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang 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., Huang JY; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Zhang M; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Chen C; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Fan LY; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Ma QY; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., He CY; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Chen SN; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Jiang Y; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Li YM; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Ning CB; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Zhang FW; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Wang WZ; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Liu YZ; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Zhang H; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Jin M; Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Wang XY; 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., Han JX; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Xiong Z; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Cai M; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Huang CQ; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China., Yang XJ; Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China., Zhu X; Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China., Zhu Y; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China., Miao XP; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China. xpmiao@whu.edu.cn.; Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China. xpmiao@whu.edu.cn.; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. xpmiao@whu.edu.cn.; Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China. xpmiao@whu.edu.cn., Zhang SK; 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. shaokaizhang@126.com., Wei YC; Department of Gastrointestinal Oncology, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. weiyongchang@whu.edu.cn., Tian JB; Department of Epidemiology and Biostatistics, School of Public Health, Research Center of Public Health, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China. tianjb@whu.edu.cn.; Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China. tianjb@whu.edu.cn.; 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. tianjb@whu.edu.cn.
Jazyk: angličtina
Zdroj: Military Medical Research [Mil Med Res] 2024 Jun 11; Vol. 11 (1), pp. 36. Date of Electronic Publication: 2024 Jun 11.
DOI: 10.1186/s40779-024-00539-2
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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