Enhancer RNAs in cancer: regulation, mechanisms and therapeutic potential

Lee, Joo-Hyung; Xiong, Feng; Li, Wenbo

doi:10.1080/15476286.2020.1712895

Cited by 73 publications

(84 citation statements)

References 123 publications

(257 reference statements)

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“…eRNAs have attracted particular interest due to their potential roles in mediating enhancer functions and gene transcription associated with cancers [ 22 ]. The aim of the present study is to explore the eRNAs as prognostic related biomarker in OV.…”

Section: Discussionmentioning

confidence: 99%

FOXP4-AS1 is a favorable prognostic-related enhancer RNA in ovarian cancer

et al. 2021

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Ovarian cancer (OV) is a main cause of death worldwide in female reproductive system malignancies. Enhancer RNAs (eRNAs) are derived from the transcription of enhancers and has attracted increasing attention in cancers recently. However, the biological functions and clinical significance of eRNAs in OV have not been well described presently. We used an integrated data analysis to identify prognostic-related eRNAs in OV. Tissue-specific enhancer-derived RNAs and their regulating genes were considered as putative eRNA-target pairs using the computational pipeline PreSTIGE. Gene expression profiles and clinical data of OV and 32 other cancer types were obtained from the UCSC Xena platform. Altogether, 71 eRNAs candidates showed significant correlation with overall survival of OV samples (Kaplan-Meier log-rank test, p < 0.05). Among which, 23 ones were determined to be correlated with their potential target genes (Spearman’s r > 0.3, p < 0.001). It was found that among the 23 prognostic-related eRNAs, the expression of FOXP4-AS1 has the highest positive correlation with its predicted target gene FOXP4 (Spearman’s r = 0.61). Moreover, the results were further validated by RT-qPCR analysis in an independent OV cohort. Our results suggested the eRNA FOXP4-AS1 expression index may be a favorable independent prognostic bio-marker candidate in OV.

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Section: Discussionmentioning

confidence: 99%

FOXP4-AS1 is a favorable prognostic-related enhancer RNA in ovarian cancer

et al. 2021

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“…As distal genomic elements, enhancers can provide DNA binding motifs to recruit transcription factors (TFs) and regulate target genes 12 . The enhancer malfunction may induce genetic and epigenetic alterations, which in turn activate oncogene expression and drive tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…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

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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.

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“…Based on this physiological process, a series of works [ 18 , 19 ] confirmed that the promoter-proximal pausing of Pol II is a crucial postrecruitment and rate-limiting step for gene regulation. In addition, eRNA transcription serves as a robust indicator of enhancer activation, and have potential roles in mediating enhancer functions and gene transcription [ 20 – 22 ], which can be applied to understanding the transcriptional regulation of disease, like tumorigenesis [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Early-life undernutrition induces enhancer RNA remodeling in mice liver

Wang

Mao

Zhao

et al. 2021

Epigenetics & Chromatin

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Background Maternal protein restriction diet (PRD) increases the risk of metabolic dysfunction in adulthood, the mechanisms during the early life of offspring are still poorly understood. Apart from genetic factors, epigenetic mechanisms are crucial to offer phenotypic plasticity in response to environmental situations and transmission. Enhancer-associated noncoding RNAs (eRNAs) transcription serves as a robust indicator of enhancer activation, and have potential roles in mediating enhancer functions and gene transcription. Results Using global run-on sequencing (GRO-seq) of nascent RNA including eRNA and total RNA sequencing data, we show that early-life undernutrition causes remodeling of enhancer activity in mouse liver. Differentially expressed nascent active genes were enriched in metabolic pathways. Besides, our work detected a large number of high confidence enhancers based on eRNA transcription at the ages of 4 weeks and 7 weeks, respectively. Importantly, except for ~ 1000 remodeling enhancers, the early-life undernutrition induced instability of enhancer activity which decreased in 4 weeks and increased in adulthood. eRNA transcription mainly contributes to the regulation of some important metabolic enzymes, suggesting a link between metabolic dysfunction and enhancer transcriptional control. We discovered a novel eRNA that is positively correlated to the expression of circadian gene Cry1 with increased binding of epigenetic cofactor p300. Conclusions Our study reveals novel insights into mechanisms of metabolic dysfunction. Enhancer activity in early life acts on metabolism-associated genes, leading to the increased susceptibility of metabolic disorders.

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Enhancer RNAs in cancer: regulation, mechanisms and therapeutic potential

Cited by 73 publications

References 123 publications

FOXP4-AS1 is a favorable prognostic-related enhancer RNA in ovarian cancer

FOXP4-AS1 is a favorable prognostic-related enhancer RNA in ovarian cancer

Identification of the prognostic Enhancer RNA in bladder cancer bone metastasis

Early-life undernutrition induces enhancer RNA remodeling in mice liver

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