Transcriptional landscape and clinical utility of enhancer RNAs for eRNA-targeted therapy in cancer

Zhang, Zhao; Lee, Joo-Hyung; Ruan, Hang; Ye, Youqiong; Krakowiak, Joanna; Hu, Qingsong; Yu, Xiang; Gong, Jing; Zhou, Bingying; Wang, Li; Lin, Chunru; Diao, Lixia; Mills, Gordon B.; Li, Wenbo; Han, Leng

doi:10.1038/s41467-019-12543-5

Cited by 192 publications

(300 citation statements)

References 63 publications

Supporting

Mentioning

277

Contrasting

Order By: Relevance

“…Recently, the clinical importance of enhancers have been widely recognized, as shown in IBD (Boyd et al, 2018) and cancer studies (Zhang et al, 2019). Nevertheless, the functional roles of variants on or near enhancers are unclear, and only a few enhancer RNA QTL studies in LCL using limited number of subjects (154 European (Garieri et al, 2017) and 69 Yoruban (Kristjánsdóttir et al, 2018)) have been conducted.…”

Section: Discussionmentioning

confidence: 99%

Predicting cell-type-specific non-coding RNA transcription from genome sequence

Koido

Hon

Koyama

et al. 2020

Preprint

View full text Add to dashboard Cite

Transcription is regulated through complex mechanisms involving non-coding RNAs (ncRNAs).However, because transcription of ncRNAs, especially enhancer RNAs, is often low and cell type-specific, its dependency on genotype remains largely unexplored. Here, we developed mutation effect prediction on ncRNA transcription (MENTR), a quantitative machine learning 5 framework reliably connecting genetic associations with expression of ncRNAs, resolved to the level of cell type. MENTR-predicted mutation effects on ncRNA transcription were concordant with estimates from previous genetic studies in a cell type-dependent manner. We inferred reliable causal variants from 41,223 GWAS variants, and proposed 7,775 enhancers and 3,548 long-ncRNAs as complex trait-associated ncRNAs in 348 major human primary cells and tissues, 10 including plausible enhancer-mediated functional alterations in single-variant resolution in Crohn's disease. In summary, we present new resources for discovering causal variants, the biological mechanisms driving complex traits, and the sequence-dependency of ncRNA regulation in relevant cell types. (145/150 words)

show abstract

Section: Discussionmentioning

confidence: 99%

Predicting cell-type-specific non-coding RNA transcription from genome sequence

Koido

Hon

Koyama

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In the current study, the normalized gene expression pro le of eRNA in BLCA (annotated by Ensemble ID) were downloaded from the eRic (enhancer RNA in cancers)database (https://hanlab.uth.edu/eRic/) 11 . In addition, the o cial gene symbol of each eRNA was identi ed by ChIPseeker packageaccordingtothelocationinhg38 genome 13 .…”

Section: The Erna Expression Matrix Extractionmentioning

confidence: 99%

“…The malfunction of enhancers may induce genetic and epigenetic alterations, and subsequently drive tumorigenesis and recurrence in many cancers 9,10 . Enhancer RNAs (eRNAs), a type of noncoding RNAs transcribed from the enhancer, help to explore the mechanisms of enhancers and also participate in cancer development 11 . Its expression is also various in different tumor types and individual patients, thus may serve as potential diagnosis markers or therapeutic targets 12 .…”

Section: Introductionmentioning

confidence: 99%

Identification of the prognostic Enhancer RNA in bladder cancer bone metastasis

Hao

Yan

Zheng

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Bladder urothelial carcinoma (BLCA), one of the most common urinary system malignancies, has a high morbidity and metastasis rate. The enhancer RNAs (eRNAs), are derived from enhancer regions and contribute to enhancer function, whereas their roles in BLCA tumorigenesis and bone metastasis are still unclear.Method The RNA sequencing data of patients with BLCA were retrieved from The Cancer Genome Atlas (TCGA) databases and the normalized gene expression profile of eRNA in BLCA (annotated by Ensemble ID) were downloaded from the eRic database. The differential expression eRNAs and genes were evaluated and identified between primary BLCA with and without bone metastasis. The prognostic bone metastasis-specific eRNAs (PBMSEs) were screened by Lasso regression, and based on them, the risk scores were identified and predict models were constructed. Their accuracy were tested by the area under the curve (AUC) of the receiver operator characteristic (ROC) curve. Additionally, in order to explore the bone metastasis-specific regulation network, the relationship among key PBMSEs, differentially expressed target genes of eRNAs and signaling pathways were identified by Pearson correlation analysis. ResultsA total of 832 eRNAs were detected, with 37 PBMSEs annotated by Ensemble ID in univariate Cox regression analysis. Based on them, the first prediction model was constructed with the AUC of 0.920. Besides, we uncovered 166 DEGs between primary BLCA with and without bone metastasis. A total of 23 eRNAs and 109 target genes annotated by official gene symbol were uncovered in which31 PBMSEs and target genes revealed prognostic. Based on them, another prediction model was constructed with the AUC of 0.742. Moreover, we identified EMP1 as a PBMSE which regulated the target genes of APOLD1 and GPRC5A, and tumorigenesis-related pathways of KRAS signaling, inflammatory response, IL2-stat5 signaling and epithelial mesenchymal transition (EMT).Conclusion Our study identifies eRNAs as reliable indexes for prognosis and bone metastasis prediction in BLCA patients and provides well-applied prediction models for them. The bone metastasis-specific regulation network was also explored in which PBMSE (EMP1) could mediate target genes (APOLD1, GPRC5A) and tumorigenesis-related pathways (KRAS signaling, inflammatory response, EMT) in the tumorigenesis and bone metastasis of BLCA.

show abstract

“…It is important to explore the sequence characteristics of the miRes to conduct further identification of enhancer-miRNA interactions. Previously, it was reported that eRNA can be used as a trans-acting element to participate in the regulation of target genes (14). Consequently, the human GENCODE annotation was first used to investigate the transcript types of the distal and proximal regulatory miRes.…”

Section: There Are Significant Differences In the Sequence Characterimentioning

confidence: 99%

Genome-wide identification and analysis of enhancer regulated microRNAs across 31 human cancers

Tang

Lang

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

Enhancers are cis-regulatory DNA elements that positively regulate the transcription of target genes in a tissue-specific manner and dysregulation in various diseases such as cancer. Recent studies showed that enhancers can regulate miRNAs and participate in the biological synthesis of miRNAs. However, the network of enhancer-regulated miRNAs across multiple cancers is still unclear. Here, a total of 2,418 proximal enhancer-miRNA interactions and 1,280 distal enhancer-miRNA interactions were identified through the integration of genomic distance, co-expression, and 3D genome data in 31 cancers. The results showed that both proximal and distal interactions exhibited significant tissue-specific feature and there was a noteworthy positive correlation between the expression of miRNA and the number of regulated enhancers in most tissues. Furthermore, it was found that there was a high correlation between the formation of enhancer-miRNA pairs and the expression of eRNAs whether in distal or proximal regulation. The characteristics analysis showed that miRes (enhancers that regulated miRNAs) and non-miRes presented significant differences in sequence conservation, GC content and histone modification signatures. Notably, GC content, H3K4me1, H3K36me3 were present differently between distal regulation and proximal regulation, suggesting they might participate in chromosome looping of enhancer-miRNA interactions. Finally, we introduced a case study, enhancer: chr1:1186391-1186507~miR-200a was highly relevant to the survival of thyroid cancer patients and a cis-eQTL SNP on enhancer affected the expression TNFRSF18 gene as a tumor suppressor.

show abstract

Transcriptional landscape and clinical utility of enhancer RNAs for eRNA-targeted therapy in cancer

Cited by 192 publications

References 63 publications

Predicting cell-type-specific non-coding RNA transcription from genome sequence

Predicting cell-type-specific non-coding RNA transcription from genome sequence

Identification of the prognostic Enhancer RNA in bladder cancer bone metastasis

Genome-wide identification and analysis of enhancer regulated microRNAs across 31 human cancers

Contact Info

Product

Resources

About