{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:46:32Z","timestamp":1760150792297,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,30]],"date-time":"2023-12-30T00:00:00Z","timestamp":1703894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute (USA)","doi-asserted-by":"publisher","award":["R01ES030993","P30CA240139"],"award-info":[{"award-number":["R01ES030993","P30CA240139"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Significant advances have been achieved in understanding the critical role of enhancer RNAs (eRNAs) in the complex field of gene regulation. However, notable uncertainty remains concerning the biology of eRNAs, highlighting the need for continued research to uncover their exact functions in cellular processes and diseases. We present a comprehensive study to scrutinize mutation density patterns, mutation strand bias, and mutation burden in eRNAs across multiple cancer types. Our findings reveal that eRNAs exhibit mutation strand bias akin to that observed in protein-coding RNAs. We also identified a novel pattern, in which mutation density is notably diminished around the central region of the eRNA, but conspicuously elevated towards both the beginning and end. This pattern can be potentially explained by a mechanism involving heightened transcriptional activity and the activation of transcription-coupled repair. The central regions of the eRNAs appear to be more conserved, hinting at a potential mechanism preserving their structural and functional integrity, while the extremities may be more susceptible to mutations due to increased exposure. The evolutionary trajectory of this mutational pattern suggests a nuanced adaptation in eRNAs, where stability at their core coexists with flexibility at their extremities, potentially facilitating their diverse interactions with other genetic entities.<\/jats:p>","DOI":"10.3390\/ijms25010534","type":"journal-article","created":{"date-parts":[[2023,12,31]],"date-time":"2023-12-31T06:37:12Z","timestamp":1704004632000},"page":"534","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Comprehensive Pan-Cancer Mutation Density Patterns in Enhancer RNA"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3953-1664","authenticated-orcid":false,"given":"Troy","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Public Health and Sciences, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Public Health and Sciences, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Limin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Public Health and Sciences, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9944-5426","authenticated-orcid":false,"given":"Yongsheng","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Biology, Eastern Michigan University, Ypsilanti, MI 48197, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5252-3960","authenticated-orcid":false,"given":"Yan","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Public Health and Sciences, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1056\/NEJMra072367","article-title":"Oncogenes and cancer","volume":"358","author":"Croce","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.molcel.2011.08.018","article-title":"Molecular Mechanisms of Long Noncoding RNAs","volume":"43","author":"Wang","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1080\/15476286.2020.1712895","article-title":"Enhancer RNAs in cancer: Regulation, mechanisms and therapeutic potential","volume":"17","author":"Lee","year":"2020","journal-title":"RNA Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-genet-110711-155459","article-title":"Noncoding Transcription at Enhancers: General Principles and Functional Models","volume":"46","author":"Natoli","year":"2012","journal-title":"Annu. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1101\/gad.308619.117","article-title":"The degree of enhancer or promoter activity is reflected by the levels and directionality of eRNA transcription","volume":"32","author":"Mikhaylichenko","year":"2018","journal-title":"Genes Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4562","DOI":"10.1038\/s41467-019-12543-5","article-title":"Transcriptional landscape and clinical utility of enhancer RNAs for eRNA-targeted therapy in cancer","volume":"10","author":"Zhang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4174","DOI":"10.1158\/0008-5472.CAN-20-4010","article-title":"Implications of Enhancer Transcription and eRNAs in Cancer","volume":"81","author":"Adhikary","year":"2021","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Stasevich, E.M., Uvarova, A.N., Murashko, M.M., Khabusheva, E.R., Sheetikov, S.A., Prassolov, V.S., Kuprash, D.V., Demin, D.E., and Schwartz, A.M. (2022). Enhancer RNA AL928768.3 from the IGH Locus Regulates MYC Expression and Controls the Proliferation and Chemoresistance of Burkitt Lymphoma Cells with IGH\/MYC Translocation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094624"},{"key":"ref_9","first-page":"D58","article-title":"EnhancerAtlas 2.0: An updated resource with enhancer annotation in 586 tissue\/cell types across nine species","volume":"48","author":"Gao","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"D106","DOI":"10.1093\/nar\/gky864","article-title":"HACER: An atlas of human active enhancers to interpret regulatory variants","volume":"47","author":"Wang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Song, C., Zhang, G., Mu, X., Feng, C., Zhang, Q., Song, S., Zhang, Y., Yin, M., Zhang, H., and Tang, H. (2023). eRNAbase: A comprehensive database for decoding the regulatory eRNAs in human and mouse. Nucleic Acids Res., gkad925.","DOI":"10.1093\/nar\/gkad925"},{"key":"ref_12","first-page":"D51","article-title":"ENdb: A manually curated database of experimentally supported enhancers for human and mouse","volume":"48","author":"Bai","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1038\/nsmb.2085","article-title":"Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters","volume":"18","author":"Koch","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nature09033","article-title":"Widespread transcription at neuronal activity-regulated enhancers","volume":"465","author":"Kim","year":"2010","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/465173a","article-title":"TRANSCRIPTION Enhancers make non-coding RNA","volume":"465","author":"Ren","year":"2010","journal-title":"Nature"},{"key":"ref_16","first-page":"413","article-title":"Impacts of somatic mutations on gene expression: An association perspective","volume":"18","author":"Jia","year":"2017","journal-title":"Brief. Bioinform."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1093\/bib\/bbz084","article-title":"MutEx: A multifaceted gateway for exploring integrative pan-cancer genomic data","volume":"21","author":"Ping","year":"2020","journal-title":"Brief. Bioinform."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yu, H., Jiang, L., Li, C.I., Ness, S., Piccirillo, S.G.M., and Guo, Y. (2023). Somatic mutation effects diffused over microRNA dysregulation. Bioinformatics, 39.","DOI":"10.1093\/bioinformatics\/btad520"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1093\/nar\/gkab877","article-title":"SBSA: An online service for somatic binding sequence annotation","volume":"50","author":"Jiang","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1126\/science.aao0535","article-title":"Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism","volume":"357","author":"Chiba","year":"2017","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"He, H., Li, W., Wu, D., Nagy, R., Liyanarachchi, S., Akagi, K., Jendrzejewski, J., Jiao, H., Hoag, K., and Wen, B. (2013). Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance. PLoS ONE, 8.","DOI":"10.1371\/annotation\/1cd4e899-2184-497b-b659-de1722b6d402"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.7150\/jca.25829","article-title":"Enhancer RNAs (eRNAs): New Insights into Gene Transcription and Disease Treatment","volume":"9","author":"Ding","year":"2018","journal-title":"J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/nrg3458","article-title":"Enhancers: Five essential questions","volume":"14","author":"Pennacchio","year":"2013","journal-title":"Nat. Rev. Genet."},{"key":"ref_24","first-page":"1930","article-title":"Surveying mutation density patterns around specific genomic features","volume":"32","author":"Yu","year":"2022","journal-title":"Genome Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4887","DOI":"10.1016\/j.csbj.2023.09.027","article-title":"Mutation density analyses on long noncoding RNA reveal comparable patterns to protein-coding RNA and prognostic value","volume":"21","author":"Zhang","year":"2023","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/nature17437","article-title":"Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes","volume":"532","author":"Perera","year":"2016","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1042\/EBC20200014","article-title":"Enhancer RNA: Biogenesis, function, and regulation","volume":"64","author":"Ye","year":"2020","journal-title":"Essays Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1158\/2159-8290.CD-20-0522","article-title":"Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors","volume":"10","author":"Sha","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wang, L., Chen, F., Liu, R., Shi, L., Zhao, G., and Yan, Z. (2021). Gene expression and immune infiltration in melanoma patients with different mutation burden. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-08083-1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41588-020-00752-4","article-title":"The association between tumor mutational burden and prognosis is dependent on treatment context","volume":"53","author":"Valero","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kim, T.K., Hemberg, M., and Gray, J.M. (2015). Enhancer RNAs: A Class of Long Noncoding RNAs Synthesized at Enhancers. Cold Spring Harb. Perspect. Biol., 7.","DOI":"10.1101\/cshperspect.a018622"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1101\/gr.225755.117","article-title":"Enhancer RNA profiling predicts transcription factor activity","volume":"28","author":"Azofeifa","year":"2018","journal-title":"Genome Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5051","DOI":"10.4049\/jimmunol.166.8.5051","article-title":"Increased transcription levels induce higher mutation rates in a hypermutating cell line","volume":"166","author":"Bachl","year":"2001","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1158\/2159-8290.CD-21-0385","article-title":"EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma","volume":"12","author":"Durbin","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"108373","DOI":"10.1016\/j.celrep.2020.108373","article-title":"Rapid and Scalable Profiling of Nascent RNA with fastGRO","volume":"33","author":"Barbieri","year":"2020","journal-title":"Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1038\/nprot.2016.086","article-title":"Base-pair-resolution genome-wide mapping of active RNA polymerases using precision nuclear run-on (PRO-seq)","volume":"11","author":"Mahat","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/s41587-022-01211-7","article-title":"A comparison of experimental assays and analytical methods for genome-wide identification of active enhancers","volume":"40","author":"Yao","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1093\/bioinformatics\/btq033","article-title":"BEDTools: A flexible suite of utilities for comparing genomic features","volume":"26","author":"Quinlan","year":"2010","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/534\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:44:55Z","timestamp":1760132695000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/534"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,30]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ijms25010534"],"URL":"https:\/\/doi.org\/10.3390\/ijms25010534","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,12,30]]}}}