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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

TitleFunctional dissection of an IFN-α/β receptor 1 promoter variant that confers higher risk to chronic hepatitis B virus infection
Authors
KeywordsHBV infection
IFNAR1
SNP
Transcription regulation
Issue Date2009
PublisherElsevier 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?
AbstractBackground/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 Identifierhttp://hdl.handle.net/10722/125126
ISSN
2015 Impact Factor: 10.59
2015 SCImago Journal Rankings: 4.570
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants Council of Hong Kong SAR
University Development Fund of the University of Hong Kong
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 FieldValueLanguage
dc.contributor.authorZhou, Jen_HK
dc.contributor.authorHuang, JDen_HK
dc.contributor.authorPoon, VKMen_HK
dc.contributor.authorChen, DQen_HK
dc.contributor.authorChan, CCSen_HK
dc.contributor.authorNg, Fen_HK
dc.contributor.authorGuan, XYen_HK
dc.contributor.authorWatt, RMen_HK
dc.contributor.authorLu, Len_HK
dc.contributor.authorYuen, KYen_HK
dc.contributor.authorZheng, BJen_HK
dc.date.accessioned2010-10-31T11:12:52Z-
dc.date.available2010-10-31T11:12:52Z-
dc.date.issued2009en_HK
dc.identifier.citationJournal Of Hepatology, 2009, v. 51 n. 2, p. 322-332en_HK
dc.identifier.issn0168-8278en_HK
dc.identifier.urihttp://hdl.handle.net/10722/125126-
dc.description.abstractBackground/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.languageengen_HK
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhepen_HK
dc.relation.ispartofJournal of Hepatologyen_HK
dc.subjectHBV infectionen_HK
dc.subjectIFNAR1en_HK
dc.subjectSNPen_HK
dc.subjectTranscription regulationen_HK
dc.subject.meshAlleles-
dc.subject.meshHepatitis B, Chronic - genetics - immunology - metabolism-
dc.subject.meshPolymorphism, Single Nucleotide-
dc.subject.meshPromoter Regions, Genetic-
dc.subject.meshReceptor, Interferon alpha-beta - genetics-
dc.titleFunctional dissection of an IFN-α/β receptor 1 promoter variant that confers higher risk to chronic hepatitis B virus infectionen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://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.emailZhou, J:jiezhou@hku.hken_HK
dc.identifier.emailHuang, JD:jdhuang@hkucc.hku.hken_HK
dc.identifier.emailGuan, XY:xyguan@hkucc.hku.hken_HK
dc.identifier.emailWatt, RM:rmwatt@hku.hken_HK
dc.identifier.emailLu, L:liweilu@hkucc.hku.hken_HK
dc.identifier.emailYuen, KY:kyyuen@hkucc.hku.hken_HK
dc.identifier.emailZheng, BJ:bzheng@hkucc.hku.hken_HK
dc.identifier.authorityZhou, J=rp01412en_HK
dc.identifier.authorityHuang, JD=rp00451en_HK
dc.identifier.authorityGuan, XY=rp00454en_HK
dc.identifier.authorityWatt, RM=rp00043en_HK
dc.identifier.authorityLu, L=rp00477en_HK
dc.identifier.authorityYuen, KY=rp00366en_HK
dc.identifier.authorityZheng, BJ=rp00353en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.jhep.2009.03.020en_HK
dc.identifier.pmid19501422-
dc.identifier.scopuseid_2-s2.0-67649202178en_HK
dc.identifier.hkuros162463en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-67649202178&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume51en_HK
dc.identifier.issue2en_HK
dc.identifier.spage322en_HK
dc.identifier.epage332en_HK
dc.identifier.eissn1600-0641-
dc.identifier.isiWOS:000268349000009-
dc.publisher.placeNetherlandsen_HK
dc.identifier.scopusauthoridZhou, J=7405550443en_HK
dc.identifier.scopusauthoridHuang, JD=8108660600en_HK
dc.identifier.scopusauthoridPoon, VKM=6603703384en_HK
dc.identifier.scopusauthoridChen, DQ=26634742000en_HK
dc.identifier.scopusauthoridChan, CCS=16021156900en_HK
dc.identifier.scopusauthoridNg, F=7103125273en_HK
dc.identifier.scopusauthoridGuan, XY=7201463221en_HK
dc.identifier.scopusauthoridWatt, RM=7102907536en_HK
dc.identifier.scopusauthoridLu, L=7403963552en_HK
dc.identifier.scopusauthoridYuen, KY=36078079100en_HK
dc.identifier.scopusauthoridZheng, BJ=7201780588en_HK

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