Genome-wide enhancer RNA profiling adds molecular links between genetic variation and human cancers.
ENSR00000155786
SENP7
Enhancer RNA
Genome-wide association study (GWAS)
eRNA quantitative trait loci (eRNAQTLs)
Journal
Military Medical Research
ISSN: 2054-9369
Titre abrégé: Mil Med Res
Pays: England
ID NLM: 101643181
Informations de publication
Date de publication:
11 Jun 2024
11 Jun 2024
Historique:
received:
21
07
2023
accepted:
17
05
2024
medline:
12
6
2024
pubmed:
12
6
2024
entrez:
11
6
2024
Statut:
epublish
Résumé
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. 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. 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 Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSION
CONCLUSIONS
Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.
Identifiants
pubmed: 38863031
doi: 10.1186/s40779-024-00539-2
pii: 10.1186/s40779-024-00539-2
doi:
Substances chimiques
RNA
63231-63-0
Enhancer RNAs
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
36Subventions
Organisme : The Program of National Natural Science Foundation of China
ID : NSFC-82103929
Organisme : The Program of National Natural Science Foundation of China
ID : NSFC-82273713
Organisme : Young Elite Scientists Sponsorship Program by CAST
ID : 2022QNRC001
Organisme : Distinguished Young Scholars of China
ID : NSFC-81925032
Organisme : Key Program of National Natural Science Foundation of China
ID : NSFC-82130098
Organisme : Fundamental Research Funds for the Central Universities
ID : 2042022rc0026
Organisme : Fundamental Research Funds for the Central Universities
ID : 2042023kf1005
Organisme : Fundamental Research Funds for the Central Universities
ID : WHU:2042022kf1205
Organisme : Fundamental Research Funds for the Central Universities
ID : WHU: 2042022kf1031
Organisme : Knowledge Innovation Program of Wuhan
ID : whkxjsj011
Organisme : Knowledge Innovation Program of Wuhan
ID : 2023020201010073
Organisme : Youth Program of National Natural Science Foundation of China
ID : NSFC-82003547
Organisme : Program of Health Commission of Hubei Province
ID : WJ2023M045
Organisme : National Science Fund for Excellent Young Scholars
ID : NSFC-82322058
Organisme : National Science Fund for Distinguished Young Scholars of Hubei Province of China
ID : 2023AFA046
Organisme : Science and Technology Innovation Seed Fund of Zhongnan Hospital of Wuhan University
ID : znpy2019060
Informations de copyright
© 2024. The Author(s).
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