Differential HFE Gene Expression Is Regulated by Alternative Splicing in Human Tissues 英文参考文献.docVIP

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Differential HFE Gene Expression Is Regulated by Alternative Splicing in Human Tissues 英文参考文献.doc

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Differential HFE Gene Expression Is Regulated by Alternative Splicing in Human Tissues 英文参考文献

DifferentialHFEGeneExpressionIsRegulatedby AlternativeSplicinginHumanTissues RuteMartins.,BrunoSilva.,DanielaProenc?a,PaulaFaustino* DepartamentodeGene′tica,InstitutoNacionaldeSau′deDr.RicardoJorge,Lisboa,Portugal Abstract Background: The pathophysiology of HFE-derived Hereditary Hemochromatosis and the function of HFE protein in iron homeostasis remain uncertain. Also, the role of alternative splicing in HFE gene expression regulation and the possible function of the corresponding protein isoforms are still unknown. The aim of this study was to gain insights into the physiologicalsignificanceofthesealternativeHFEvariants. Methodology/PrincipalFindings:AlternativelysplicedHFEtranscriptsindiversehumantissueswereidentifiedbyRT-PCR, cloningandsequencing.TotalHFEtranscripts,aswellastwoalternativesplicingtranscriptswerequantifiedusingareal- time PCR methodology. Intracellular localization, trafficking and protein association of GFP-tagged HFE protein variants wereanalysed in transiently transfected HepG2cells by immunoprecipitation andimmunofluorescenceassays. Alterna- tively spliced HFE transcripts present both level- and tissue-specificity. Concerning the exon 2 skipping and intron 4 inclusiontranscripts,theliverpresentsthelowestrelativelevel,whileduodenumpresentsoneofthehighestamounts.The protein resulting from exon 2 skipping transcript is unable to associate with b2M andTfR1 andreveals anER retention. Conversely,theintron4inclusiontranscriptgivesrisetoatruncated,solubleprotein(sHFE)thatismostlysecretedbycells tothemediuminassociationwithb2M. Conclusions/Significance: HFE gene post-transcriptional regulation is clearly affected by a tissue-dependent alternative splicingmechanism.Amongthecorrespondingproteins,asHFEisoformstandsout,whichuponbeingsecretedintothe bloodstream,mayactinremotetissues.ItcouldbeeitheranagonistorantagonistofthefulllengthHFE,throughhepcidin expressionregulationintheliverorbycontrollingdietaryironabsorptionintheduodenum. Citation:MartinsR,SilvaB,