Enhancer RNA Transcriptome‐Wide Association Study Reveals a Distinctive Class of Pan‐Cancer Susceptibility eRNAs
Abstract Many cancer risk variants are located within enhancer regions and lack sufficient molecular interpretation. Here, we constructed the first comprehensive atlas of enhancer RNA (eRNA)‐mediated genetic effects from 28 033 RNA sequencing samples across 11 606 individuals, identifying 21 073 eRN...
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202411974 |
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| author | Wenyan Chen Zeyang Wang Yinuo Wang Jianxiang Lin Shuxin Chen Hui Chen Xuelian Ma Xudong Zou Xing Li Yangmei Qin Kewei Xiong Xixian Ma Qi Liao Yunbo Qiao Lei Li |
| author_facet | Wenyan Chen Zeyang Wang Yinuo Wang Jianxiang Lin Shuxin Chen Hui Chen Xuelian Ma Xudong Zou Xing Li Yangmei Qin Kewei Xiong Xixian Ma Qi Liao Yunbo Qiao Lei Li |
| author_sort | Wenyan Chen |
| collection | DOAJ |
| description | Abstract Many cancer risk variants are located within enhancer regions and lack sufficient molecular interpretation. Here, we constructed the first comprehensive atlas of enhancer RNA (eRNA)‐mediated genetic effects from 28 033 RNA sequencing samples across 11 606 individuals, identifying 21 073 eRNA quantitative trait loci (eRNA‐QTLs) significantly associated with eRNA expression. Mechanistically, eRNA‐QTLs frequently altered binding motifs of transcription factors. In addition, 28.48% of cancer risk variants are strongly colocalized with eRNA‐QTLs. A pan‐cancer eRNA‐based transcriptome‐wide association study is conducted across 23 major cancer types, identifying 626 significant cancer susceptibility eRNAs predicted to modulate cancer risk via eRNA, from which 54.90% of the eRNA target genes are overlooked by traditional gene expression studies, and most are essential for cancer cell proliferation. As proof of principle validation, the enhancer functionality of two newly identified susceptibility eRNAs, CCND1e and SNAPC1e, is confirmed through CRISPR inhibition and shRNA‐mediated knockdown, resulting in a marked decrease in the expression of their respective target genes, consequently suppressing the proliferation of prostate cancer cells. The study underscores the essential role of eRNA in unveiling new cancer susceptibility genes and establishes a strong framework for enhancing our understanding of human cancer etiology. |
| format | Article |
| id | doaj-art-ee34fb74d7684d7f93ee4cfded48fab1 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-ee34fb74d7684d7f93ee4cfded48fab12025-08-20T01:51:39ZengWileyAdvanced Science2198-38442025-04-011213n/an/a10.1002/advs.202411974Enhancer RNA Transcriptome‐Wide Association Study Reveals a Distinctive Class of Pan‐Cancer Susceptibility eRNAsWenyan Chen0Zeyang Wang1Yinuo Wang2Jianxiang Lin3Shuxin Chen4Hui Chen5Xuelian Ma6Xudong Zou7Xing Li8Yangmei Qin9Kewei Xiong10Xixian Ma11Qi Liao12Yunbo Qiao13Lei Li14Institute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaInstitute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaInstitute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaNinth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200125 ChinaInstitute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaInstitute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaInstitute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaInstitute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaInstitute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaInstitute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaInstitute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaInstitute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaSchool of Public Health Health Science Center Ningbo University Ningbo 315211 ChinaNinth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200125 ChinaInstitute of Systems and Physical Biology Shenzhen Bay Laboratory Shenzhen 518055 ChinaAbstract Many cancer risk variants are located within enhancer regions and lack sufficient molecular interpretation. Here, we constructed the first comprehensive atlas of enhancer RNA (eRNA)‐mediated genetic effects from 28 033 RNA sequencing samples across 11 606 individuals, identifying 21 073 eRNA quantitative trait loci (eRNA‐QTLs) significantly associated with eRNA expression. Mechanistically, eRNA‐QTLs frequently altered binding motifs of transcription factors. In addition, 28.48% of cancer risk variants are strongly colocalized with eRNA‐QTLs. A pan‐cancer eRNA‐based transcriptome‐wide association study is conducted across 23 major cancer types, identifying 626 significant cancer susceptibility eRNAs predicted to modulate cancer risk via eRNA, from which 54.90% of the eRNA target genes are overlooked by traditional gene expression studies, and most are essential for cancer cell proliferation. As proof of principle validation, the enhancer functionality of two newly identified susceptibility eRNAs, CCND1e and SNAPC1e, is confirmed through CRISPR inhibition and shRNA‐mediated knockdown, resulting in a marked decrease in the expression of their respective target genes, consequently suppressing the proliferation of prostate cancer cells. The study underscores the essential role of eRNA in unveiling new cancer susceptibility genes and establishes a strong framework for enhancing our understanding of human cancer etiology.https://doi.org/10.1002/advs.202411974enhancer RNAgenome‐wide association studynoncoding variantspan‐cancertranscriptome‐wide association study |
| spellingShingle | Wenyan Chen Zeyang Wang Yinuo Wang Jianxiang Lin Shuxin Chen Hui Chen Xuelian Ma Xudong Zou Xing Li Yangmei Qin Kewei Xiong Xixian Ma Qi Liao Yunbo Qiao Lei Li Enhancer RNA Transcriptome‐Wide Association Study Reveals a Distinctive Class of Pan‐Cancer Susceptibility eRNAs Advanced Science enhancer RNA genome‐wide association study noncoding variants pan‐cancer transcriptome‐wide association study |
| title | Enhancer RNA Transcriptome‐Wide Association Study Reveals a Distinctive Class of Pan‐Cancer Susceptibility eRNAs |
| title_full | Enhancer RNA Transcriptome‐Wide Association Study Reveals a Distinctive Class of Pan‐Cancer Susceptibility eRNAs |
| title_fullStr | Enhancer RNA Transcriptome‐Wide Association Study Reveals a Distinctive Class of Pan‐Cancer Susceptibility eRNAs |
| title_full_unstemmed | Enhancer RNA Transcriptome‐Wide Association Study Reveals a Distinctive Class of Pan‐Cancer Susceptibility eRNAs |
| title_short | Enhancer RNA Transcriptome‐Wide Association Study Reveals a Distinctive Class of Pan‐Cancer Susceptibility eRNAs |
| title_sort | enhancer rna transcriptome wide association study reveals a distinctive class of pan cancer susceptibility ernas |
| topic | enhancer RNA genome‐wide association study noncoding variants pan‐cancer transcriptome‐wide association study |
| url | https://doi.org/10.1002/advs.202411974 |
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