Regulation of Clock-Controlled Genes in Mammals 英文参考文献.docVIP

RegulationofClock-ControlledGenesinMammals KatarzynaBozek1,2.,AngelaRelo′gio2.,SzymonM.Kielbasa3,MarkusHeine4,ChristofDame5 ,Achim Kramer4,HanspeterHerzel2* 1Max Planck Institute for Informatics, Saarbru¨cken, Germany, 2Institute for Theoretical Biology, Humboldt University, Berlin, Germany, 3Max Planck Institute for MolecularGenetics,Berlin,Germany,4LaboratoryofChronobiology,Charite′-Universita¨smedizinBerlin,Berlin,Germany,5DepartmentofNeonatology,CampusVirchow- KlinikumCharite′ -Universita¨tsmedizin Berlin,Berlin,Germany Abstract The complexity of tissue- and day time-specific regulation of thousands of clock-controlled genes (CCGs) suggests that many regulatory mechanisms contribute to the transcriptional output of the circadian clock. We aim to predict these mechanismsusingalargescalepromoteranalysisofCCGs. Ourstudyisbasedonameta-analysisofDNA-arraydatafrom rodenttissues.Wesearchedinthepromoterregionsof2065CCGsforhighlyoverrepresentedtranscriptionfactorbinding sites.InordertocompensatetherelativelyhighGC-contentofCCGpromoters,anovelbackgroundmodeltoavoidabias towardsGC-richmotifswasemployed.Wefoundthatmanyofthetranscriptionfactorswithoverrepresentedbindingsites in CCG promoters exhibit themselves circadian rhythms. Among the predicted factors are known regulators such as CLOCK:BMAL1, DBP, HLF, E4BP4, CREB, RORa and the recently described regulators HSF1, STAT3, SP1 and HNF-4a . As additionalpromisingcandidatesofcircadiantranscriptionalregulatorsPAX-4,C/EBP,EVI-1,IRF,E2F,AP-1,HIF-1andNF-Y wereidentified.Moreover,GC-richmotifs(SP1,EGR,ZF5,AP-2,WT1,NRF-1)andAT-richmotifs(MEF-2,HMGIY,HNF-1,OCT- 1)aresignificantlyoverrepresentedinpromoter regionsofCCGs.Putativetissue-specificbindingsitessuchasHNF-3for liver,NKX2.5forheart orMyogeninforskeletal musclewerefound. Theregulationoftheerythropoietin (Epo)genewas analysed, which exhibits many binding sites for circadian regulators. We provide experimental evidence for its circadian regulatedexpressionintheadult