{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:44:04Z","timestamp":1760060644912,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T00:00:00Z","timestamp":1757203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of Chongqing","award":["CSTB2022NSCQ-MSX0311","cstc2020jcyj-msxmX0446","2024-27","SWU-KT22013"],"award-info":[{"award-number":["CSTB2022NSCQ-MSX0311","cstc2020jcyj-msxmX0446","2024-27","SWU-KT22013"]}]},{"name":"the General Fund of Guizhou Agricultural Science and Technology","award":["CSTB2022NSCQ-MSX0311","cstc2020jcyj-msxmX0446","2024-27","SWU-KT22013"],"award-info":[{"award-number":["CSTB2022NSCQ-MSX0311","cstc2020jcyj-msxmX0446","2024-27","SWU-KT22013"]}]},{"name":"the Fundamental Research Funds for the Central Universities","award":["CSTB2022NSCQ-MSX0311","cstc2020jcyj-msxmX0446","2024-27","SWU-KT22013"],"award-info":[{"award-number":["CSTB2022NSCQ-MSX0311","cstc2020jcyj-msxmX0446","2024-27","SWU-KT22013"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Hepatitis E virus (HEV) is one of the pathogens that cause viral hepatitis, and its clinical symptoms can manifest as acute, chronic viral hepatitis, or asymptomatic infection. Among them, swines are the main animal source of HEV. Open reading frame 3 (ORF3) is a multifunctional protein essential for swine hepatitis E virus (SHEV) infection and release, involved in biological processes such as intracellular signal transduction regulation. In our preliminary research, we utilized adenovirus-mediated overexpression of type IV SHEV ORF3 in HepG2 cells, extracted total RNA, and performed high-throughput long non coding RNAs (lncRNAs) and transcriptome sequencing. In this study, we screened and analyzed lncRNAs involved in the GO pathway: viral process (GO: 0016032), and combined them with differentially expressed mRNAs for target gene prediction. We identified two lncRNAs\u2014lncRNA AL137002 (MSTRG. 7478) and lncRNA AL049840 (MSTRG. 8427)\u2014that are associated with viral progression and have p \u2264 0.05 in HepG2 cells expressing ORF3 of porcine hepatitis E virus type IV. We predicted their five lncRNA-mRNA networks, which are lncRNA AL137002 (MSTRG. 7478)-ENST0000375440, lncRNA AL137002 (MSTRG. 7478)-ENST0000375441, lncRNA AL049840(MSTRG. 8427)-ENST0000246489, lncRNA AL049840 (MSTRG. 8427)-ENST0000554280 and lncRNA AL049840 (MSTRG. 8427)-ENST0000452929, and were used to predict their lncRNA mRNA binding sites and construct relevant molecular models. This will lay a solid foundation for further revealing the function of SHEV ORF3 and elucidating the mechanism of SHEV infection.<\/jats:p>","DOI":"10.3390\/microorganisms13092086","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T08:06:32Z","timestamp":1757318792000},"page":"2086","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bioinformatics Analysis of the Key lncRNAs of the Viral Response Pathway in HepG2 Expressing Genotype IV Swine Hepatitis E Virus ORF3"],"prefix":"10.3390","volume":"13","author":[{"given":"Hanwei","family":"Jiao","sequence":"first","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengping","family":"Wu","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingjie","family":"Wang","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi","family":"Meng","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gengxu","family":"Zhou","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Guo","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4697-8509","authenticated-orcid":false,"given":"Liting","family":"Cao","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Ministry of Agriculture and Rural Affairs, Key Laboratory of Crop Genetic Resources and Germplasm Innovation in Karst Region, Institute of Animal Husbandry and Veterinary Medicine of Guizhou Academy of Agricultural Science, Guiyang 550005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2558-3164","authenticated-orcid":false,"given":"Zhenhui","family":"Song","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5075-9272","authenticated-orcid":false,"given":"Jake","family":"Wen","sequence":"additional","affiliation":[{"name":"Center for Translational Cancer Research, Brown Foundation Institute of Molecular Medicine, 1825 Pressler St., Suite 310, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,7]]},"reference":[{"key":"ref_1","first-page":"2605","article-title":"Research progress on cross-species transmission and prevention and control techniques of hepatitis E virus","volume":"51","author":"He","year":"2024","journal-title":"China Anim. Husb. Vet. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1099\/jgv.0.000393","article-title":"Proposed reference sequences for hepatitis E virus subtypes","volume":"97","author":"Smith","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.rvsc.2021.11.015","article-title":"A systematic review and meta-analysis of hepatitis E virus (HEV) in wild boars","volume":"142","author":"Fanelli","year":"2022","journal-title":"Res. Vet. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1111\/tbed.13115","article-title":"Genetically similar hepatitis E virus strains infect both humans and wild boars in the Barcelona area, Spain, and Sweden","volume":"66","author":"Wang","year":"2019","journal-title":"Transbound. Emerg. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Primadharsini, P.P., Nagashima, S., and Okamoto, H. (2019). Genetic variability and evolution of hepatitis e virus. Viruses, 11.","DOI":"10.3390\/v11050456"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9860","DOI":"10.1073\/pnas.94.18.9860","article-title":"A novel virus in swine is closely related to the human hepatitis E virus","volume":"94","author":"Meng","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"105429","DOI":"10.1016\/j.rvsc.2024.105429","article-title":"Hepatitis E virus infection during pregnancy: Advances in animal models","volume":"180","author":"Li","year":"2024","journal-title":"Res. Vet. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jiao, F., Zhao, Y., Zhou, G., Meng, C., Wang, L., Wu, S., Li, J., Cao, L., Zhou, B., and Luo, Y. (2024). Multiple Functions of Hepatitis E Virus ORF3. Microorganisms, 12.","DOI":"10.3390\/microorganisms12071405"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e29691","DOI":"10.1002\/jmv.29691","article-title":"Multifunctional ORF3 protein of hepatitis E virus","volume":"96","author":"Li","year":"2024","journal-title":"J. Med. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"197985","DOI":"10.1016\/j.virusres.2020.197985","article-title":"Swine hepatitis E virus: Cross-species infection, pork safety and chronic infection","volume":"284","author":"Sooryanarain","year":"2020","journal-title":"Virus Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.virol.2015.09.012","article-title":"Replacement of the hepatitis E virus ORF3 protein PxxP motif with heterologous late domain motifs affects virus release via interaction with TSG101","volume":"486","author":"Kenney","year":"2015","journal-title":"Virology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6451","DOI":"10.1016\/j.cell.2024.10.024","article-title":"Small and long non-coding RNAs: Past, present, and future","volume":"187","author":"Chen","year":"2024","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.cell.2009.02.006","article-title":"Evolution and functions of long noncoding RNAs","volume":"136","author":"Ponting","year":"2009","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Jiao, H., Shuai, X., Luo, Y., Zhou, Z., Zhao, Y., Li, B., Gu, G., Li, W., Li, M., and Zeng, H. (2021). Deep Insight into Long Non-coding RNA and mRNA Transcriptome Profiling in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3. Front. Vet. Sci., 8.","DOI":"10.3389\/fvets.2021.625609"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jiao, H., Meng, C., Jiao, F., Zhou, G., Wang, L., Wu, S., Fan, C., Li, J., Cao, L., and Zhao, Y. (2025). Descriptive Comparative Transcriptomic Analysis of Genotype IV SHEV ORF3-Expressing HepG2 Cells. Microorganisms, 13.","DOI":"10.3390\/microorganisms13020412"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tang, D., Chen, M., Huang, X., Zhang, G., Zeng, L., Zhang, G., Wu, S., and Wang, Y. (2023). SRplot: A free online platform for data visualization and graphing. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0294236"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"He, Z., Liu, D., Liu, B., Zhang, P., Wang, X., Wang, G., Huang, Y., Chen, J., and Cai, R. (2025). Prevalence of hepatitis E virus in swine in China: A systematic review with meta-analysis (2004\u20132023). Front. Vet. Sci., 11.","DOI":"10.3389\/fvets.2024.1472658"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"981","DOI":"10.15212\/ZOONOSES-2022-0023","article-title":"Advances in Acute Severe Hepatitis of Unknown Etiology in Children","volume":"2","author":"Zhou","year":"2022","journal-title":"Zoonoses"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.2147\/IDR.S449221","article-title":"Hepatitis E Virus (HEV) Infection Among Immunocompromised Individuals: A Brief Narrative Review","volume":"17","author":"Alexandrova","year":"2024","journal-title":"Infect. Drug Resist."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"313","DOI":"10.14218\/JCTH.2020.00030","article-title":"HEV and HBV dual infection:a review","volume":"8","author":"Nasir","year":"2020","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"997","DOI":"10.15212\/ZOONOSES-2021-0013","article-title":"Measles-associated severe pneumonia in a patient with HBeAg-negative chronic hepatitis B: A case report","volume":"2","author":"Zhao","year":"2022","journal-title":"Zoonoses"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17086","DOI":"10.1038\/nrdp.2017.86","article-title":"Hepatitise virus infection","volume":"3","author":"Kamar","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5543","DOI":"10.3748\/wjg.v26.i37.5543","article-title":"Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment","volume":"26","author":"Aslan","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101274","DOI":"10.1016\/j.coviro.2022.101274","article-title":"Hepatitis E virus species barriers: Seeking viral and host determinants","volume":"56","author":"Kinast","year":"2022","journal-title":"Curr. Opin. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9059","DOI":"10.1128\/JVI.00593-10","article-title":"Release of genotype 1 hepatitis E virus from cultured hepatoma and polarized intestinal cells depends on open reading frame 3 protein and requires an intact PXXP motif","volume":"84","author":"Emerson","year":"2010","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1099\/vir.0.025791-0","article-title":"A PSAP motif in the ORF3 protein of hepatitis E virus is necessary for virion release from infected cells","volume":"92","author":"Nagashima","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1099\/vir.0.010561-0","article-title":"ORF3 protein of hepatitis E virus is essential for virion release from infected cells","volume":"90","author":"Yamada","year":"2009","journal-title":"J. Gen. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e0058521","DOI":"10.1128\/JVI.00585-21","article-title":"The Viral ORF3 Protein is Required for Hepatitis E Virus Apical Release and Efficient Growth in Polarized Hepatocytes and Humanized Mice","volume":"95","author":"Sari","year":"2021","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1186\/s12985-024-02576-8","article-title":"Current knowledge on the epidemiology and detection methods of hepatitis E virus in China","volume":"21","author":"Duan","year":"2024","journal-title":"Virol. J."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zahmanova, G., Takova, K., Tonova, V., Koynarski, T., Lukov, L.L., Minkov, I., Pishmisheva, M., Kotsev, S., Tsachev, I., and Baymakova, M. (2023). The Re-Emergence of Hepatitis E Virus in Europe and Vaccine Development. Viruses, 15.","DOI":"10.3390\/v15071558"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.jhep.2023.03.024","article-title":"The pressing need for a global HEV vaccine","volume":"79","author":"Peron","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Gokhale, N.S., and Horner, S.M. (2017). RNA modifications go viral. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006188"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hangauer, M.J., Vaughn, I.W., and McManus, M.T. (2013). Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003569"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Bridges, M.C., Daulagala, A.C., and Kourtidis, A. (2021). LNCcation: lncRNA localization and function. J. Cell Biol., 220.","DOI":"10.1083\/jcb.202009045"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.cell.2018.01.011","article-title":"Functional Classification and Experimental Dissection of Long Noncoding RNAs","volume":"172","author":"Kopp","year":"2018","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ncrna.2017.03.002","article-title":"Viral lncRNA: A regulatory molecule for controlling virus life cycle","volume":"2","author":"Wang","year":"2017","journal-title":"Non-Coding RNA Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.virusres.2018.02.014","article-title":"An analysis of two open reading frames (ORF3 and ORF4) of rat hepatitis E virus genome using its infectious cDNA clones with mutations in ORF3 or ORF4","volume":"249","author":"Tanggis","year":"2018","journal-title":"Virus Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Madhukar, G., Haque, M.A., Khan, S., Kim, J.J. (2025). E3 ubiquitin ligases and their therapeutic potential in disease Management. Biochem. Pharmacol., 236.","DOI":"10.1016\/j.bcp.2025.116875"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15395","DOI":"10.1074\/jbc.273.25.15395","article-title":"Two kinesin light chain genes in mice. Identification and characterization of the encoded proteins","volume":"273","author":"Rahman","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5350999","DOI":"10.1155\/2023\/5350999","article-title":"LncRNA AC040162.3 Promotes HCV-Induced T2DM Deterioration through the miRNA-223-3p\/NLRP3 Molecular Axis","volume":"2023","author":"Niu","year":"2023","journal-title":"Anal. Cell. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.virs.2023.10.002","article-title":"LncRNA NKILA inhibits HBV replication by repressing NF-\u03baB signalling activation","volume":"39","author":"Zhang","year":"2024","journal-title":"Virol. Sin."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Chi, X., Hu, J., Wang, S., Zhao, S., Mao, Y., Peng, B., Chen, J.-L., and Wang, S. (2023). LncRNA LINC02574 Inhibits Influenza A Virus Replication by Positively Regulating the Innate Immune Response. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087248"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/9\/2086\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:41:27Z","timestamp":1760035287000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/9\/2086"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,7]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["microorganisms13092086"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms13092086","relation":{},"ISSN":["2076-2607"],"issn-type":[{"type":"electronic","value":"2076-2607"}],"subject":[],"published":{"date-parts":[[2025,9,7]]}}}