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- Publisher Website: 10.1016/j.jhep.2009.03.020
- Scopus: eid_2-s2.0-67649202178
- PMID: 19501422
- WOS: WOS:000268349000009
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Article: Functional dissection of an IFN-α/β receptor 1 promoter variant that confers higher risk to chronic hepatitis B virus infection
Title | Functional dissection of an IFN-α/β receptor 1 promoter variant that confers higher risk to chronic hepatitis B virus infection | ||||||
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Authors | |||||||
Keywords | HBV infection IFNAR1 SNP Transcription regulation | ||||||
Issue Date | 2009 | ||||||
Publisher | Elsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep | ||||||
Citation | Journal Of Hepatology, 2009, v. 51 n. 2, p. 322-332 How to Cite? | ||||||
Abstract | Background/Aims: We previously demonstrated that two linked single nucleotide polymorphisms (SNPs) at -408 and -3 of type I interferon receptor 1 (IFNAR1) promoter are associated with susceptibility to chronic HBV infection. We aimed to elucidate the mechanism by which -3 and/or -408 C/T SNPs had such profound effects. Methods: A functional SNP in IFNAR1 promoter was defined by reporter gene assay, mutational analysis, flow cytometry analysis and gel shift assay. The nuclear protein binding to the essential polymorphic site was identified and its effect on transcriptional regulation of IFNAR1 was further demonstrated in a series of ex vivo and in vivo experiments. Results: We found C > T change at the -3 locus reduced the transcriptional activity of IFNAR1 promoter. High mobility group B protein 1 (HMGB1) and PARP-1 were co-recruited to the IFNAR1 promoter to regulate its transcription. We demonstrated HMGB1-binding affinity to IFNAR1 promoter was reduced in the -3T variant. Additionally, PARP-1, a cofactor for IFNAR1 transcription activation, was significantly suppressed by HBV. Conclusion: Upon HBV infection, decreased binding affinity of HMGB1 to the IFNAR1 promoter -3T variant is aggravated by the suppressed PARP-1 expression caused by HBV, resulting in a further attenuated IFNAR1 expression. This compromises the antiviral and immuno-regulatory effects of IFN-α/β, which may in turn affect the clinical outcome of HBV infection. © 2009 European Association for the Study of the Liver. | ||||||
Persistent Identifier | http://hdl.handle.net/10722/125126 | ||||||
ISSN | 2023 Impact Factor: 26.8 2023 SCImago Journal Rankings: 9.857 | ||||||
ISI Accession Number ID |
Funding Information: This work is supported by Research Grants Council of Hong Kong SAR and the University Development Fund of the University of Hong Kong. We also acknowledge Dr. Qian Wang and Dr. Jiong Bi (Sun Yat-sen University) for providing the liver tissue samples. | ||||||
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Zhou, J | en_HK |
dc.contributor.author | Huang, JD | en_HK |
dc.contributor.author | Poon, VKM | en_HK |
dc.contributor.author | Chen, DQ | en_HK |
dc.contributor.author | Chan, CCS | en_HK |
dc.contributor.author | Ng, F | en_HK |
dc.contributor.author | Guan, XY | en_HK |
dc.contributor.author | Watt, RM | en_HK |
dc.contributor.author | Lu, L | en_HK |
dc.contributor.author | Yuen, KY | en_HK |
dc.contributor.author | Zheng, BJ | en_HK |
dc.date.accessioned | 2010-10-31T11:12:52Z | - |
dc.date.available | 2010-10-31T11:12:52Z | - |
dc.date.issued | 2009 | en_HK |
dc.identifier.citation | Journal Of Hepatology, 2009, v. 51 n. 2, p. 322-332 | en_HK |
dc.identifier.issn | 0168-8278 | en_HK |
dc.identifier.uri | http://hdl.handle.net/10722/125126 | - |
dc.description.abstract | Background/Aims: We previously demonstrated that two linked single nucleotide polymorphisms (SNPs) at -408 and -3 of type I interferon receptor 1 (IFNAR1) promoter are associated with susceptibility to chronic HBV infection. We aimed to elucidate the mechanism by which -3 and/or -408 C/T SNPs had such profound effects. Methods: A functional SNP in IFNAR1 promoter was defined by reporter gene assay, mutational analysis, flow cytometry analysis and gel shift assay. The nuclear protein binding to the essential polymorphic site was identified and its effect on transcriptional regulation of IFNAR1 was further demonstrated in a series of ex vivo and in vivo experiments. Results: We found C > T change at the -3 locus reduced the transcriptional activity of IFNAR1 promoter. High mobility group B protein 1 (HMGB1) and PARP-1 were co-recruited to the IFNAR1 promoter to regulate its transcription. We demonstrated HMGB1-binding affinity to IFNAR1 promoter was reduced in the -3T variant. Additionally, PARP-1, a cofactor for IFNAR1 transcription activation, was significantly suppressed by HBV. Conclusion: Upon HBV infection, decreased binding affinity of HMGB1 to the IFNAR1 promoter -3T variant is aggravated by the suppressed PARP-1 expression caused by HBV, resulting in a further attenuated IFNAR1 expression. This compromises the antiviral and immuno-regulatory effects of IFN-α/β, which may in turn affect the clinical outcome of HBV infection. © 2009 European Association for the Study of the Liver. | en_HK |
dc.language | eng | en_HK |
dc.publisher | Elsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep | en_HK |
dc.relation.ispartof | Journal of Hepatology | en_HK |
dc.subject | HBV infection | en_HK |
dc.subject | IFNAR1 | en_HK |
dc.subject | SNP | en_HK |
dc.subject | Transcription regulation | en_HK |
dc.subject.mesh | Alleles | - |
dc.subject.mesh | Hepatitis B, Chronic - genetics - immunology - metabolism | - |
dc.subject.mesh | Polymorphism, Single Nucleotide | - |
dc.subject.mesh | Promoter Regions, Genetic | - |
dc.subject.mesh | Receptor, Interferon alpha-beta - genetics | - |
dc.title | Functional dissection of an IFN-α/β receptor 1 promoter variant that confers higher risk to chronic hepatitis B virus infection | en_HK |
dc.type | Article | en_HK |
dc.identifier.openurl | http://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0168-8278&volume=51&issue=2&spage=322&epage=332&date=2009&atitle=Functional+dissection+of+an+IFN-alfa/belta+receptor+1+promoter+variant+that+confers+higher+risk+to+chronic+hepatitis+B+virus+infection | - |
dc.identifier.email | Zhou, J:jiezhou@hku.hk | en_HK |
dc.identifier.email | Huang, JD:jdhuang@hkucc.hku.hk | en_HK |
dc.identifier.email | Guan, XY:xyguan@hkucc.hku.hk | en_HK |
dc.identifier.email | Watt, RM:rmwatt@hku.hk | en_HK |
dc.identifier.email | Lu, L:liweilu@hkucc.hku.hk | en_HK |
dc.identifier.email | Yuen, KY:kyyuen@hkucc.hku.hk | en_HK |
dc.identifier.email | Zheng, BJ:bzheng@hkucc.hku.hk | en_HK |
dc.identifier.authority | Zhou, J=rp01412 | en_HK |
dc.identifier.authority | Huang, JD=rp00451 | en_HK |
dc.identifier.authority | Guan, XY=rp00454 | en_HK |
dc.identifier.authority | Watt, RM=rp00043 | en_HK |
dc.identifier.authority | Lu, L=rp00477 | en_HK |
dc.identifier.authority | Yuen, KY=rp00366 | en_HK |
dc.identifier.authority | Zheng, BJ=rp00353 | en_HK |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1016/j.jhep.2009.03.020 | en_HK |
dc.identifier.pmid | 19501422 | - |
dc.identifier.scopus | eid_2-s2.0-67649202178 | en_HK |
dc.identifier.hkuros | 162463 | en_HK |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-67649202178&selection=ref&src=s&origin=recordpage | en_HK |
dc.identifier.volume | 51 | en_HK |
dc.identifier.issue | 2 | en_HK |
dc.identifier.spage | 322 | en_HK |
dc.identifier.epage | 332 | en_HK |
dc.identifier.eissn | 1600-0641 | - |
dc.identifier.isi | WOS:000268349000009 | - |
dc.publisher.place | Netherlands | en_HK |
dc.identifier.scopusauthorid | Zhou, J=7405550443 | en_HK |
dc.identifier.scopusauthorid | Huang, JD=8108660600 | en_HK |
dc.identifier.scopusauthorid | Poon, VKM=6603703384 | en_HK |
dc.identifier.scopusauthorid | Chen, DQ=26634742000 | en_HK |
dc.identifier.scopusauthorid | Chan, CCS=16021156900 | en_HK |
dc.identifier.scopusauthorid | Ng, F=7103125273 | en_HK |
dc.identifier.scopusauthorid | Guan, XY=7201463221 | en_HK |
dc.identifier.scopusauthorid | Watt, RM=7102907536 | en_HK |
dc.identifier.scopusauthorid | Lu, L=7403963552 | en_HK |
dc.identifier.scopusauthorid | Yuen, KY=36078079100 | en_HK |
dc.identifier.scopusauthorid | Zheng, BJ=7201780588 | en_HK |
dc.identifier.issnl | 0168-8278 | - |