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Evidence for transcript-specific epigeneticregulation of glucocorticoid-stimulated skeletalmuscle 11beta-hydroxysteroid dehydrogenase-1 activityin type 2 diabetes.doc

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Evidence for transcript-specific epigeneticregulation of glucocorticoid-stimulated skeletalmuscle 11beta-hydroxysteroid dehydrogenase-1 activityin type 2 diabetes

Inderetal.ClinicalEpigenetics2012,4:24 /content/4/1/24 RESEARCH OpenAccess Evidencefortranscript-specificepigenetic regulationofglucocorticoid-stimulatedskeletal muscle11β-hydroxysteroiddehydrogenase-1 activityintype2diabetes WarrickJInder1,2,3*,VaruniRObeyesekere1,ChristinaJang1,4andRichardSaffery5 Abstract Background:Theenzyme11β-hydroxysteroiddehydrogenasetype1(11βHSD1)convertsinactivecortisoneinto activecortisolininsulintargettissues.Inpeoplewithtype2diabetes,skeletalmuscle(SkM)11βHSD1is upregulatedbythepotentglucocorticoiddexamethasone.TheHSD11B1genehastwopromotersdesignatedP1 andP2.CCAAT/enhancer-bindingproteinbeta(C/EBPβ)isknowntoregulateexpressionof11βHSD1viatheP2 promoter.Inthisstudy,weinvestigatedthepotentialroleofalteredDNAmethylationoftheP1andP2promoters intheobserveddexamethasone-inducedupregulationofSkM11βHSD1oxoreductaseactivityinhumandiabetic subjects.SkMbiopsiesfrom15peoplewithtype2diabeteswerecollectedbeforeandaftertreatmentwithoral dexamethasone4mg/dayfor4daysandSkM11βHSD1,C/EBPβandP1andP2promoterregionmRNAlevelswere measuredbyquantitativeRT-PCR.11βHSD1oxoreductaseactivitywasquantifiedbymeasuringtheconversionof radiolabeled 3H-cortisone to cortisol by thin layer chromatography. Analysis of HSD11B1 promoter methylation (P1 and P2) was performed using Sequenom MassARRAY EpiTYPER analysis. Results: Dexamethasonetreatmentresultedinasignificantincreasein11βHSD1mRNAlevels(P=0.003), oxoreductaseactivity(P=0.017)andC/EBPβmRNA(P=0.015),andincreasedexpressionofboththeP1(P=0.008) andP2(P=0.016)promoterregions.ThedistalP1promoterregionshowedasignificantreductioninmethylation followingdexamethasone(P=0.026).Therewasasignificantnegativecorrelationbetweenthechangein methylationatthissiteandtheincrementin11βHSD1oxoreductaseactivity(r=?0.62,P=0.014). Conclusions:OurfindingsofreducedmethylationintheHSD11B1P1promoterinassociationwithincreased 11βHSD1oxoreductaseactivityimplicatecomplexmulti-promoterepigeneticmechanismsintheregulationof 11βHSD1levelsinSkM. Keywords