Equitoxic Doses of 5-Azacytidine and 5-Aza-2′Deoxycytidine Induce Diverse Immediate and Overlapping Heritable Changes in the Transcriptome 英文参考文献.docVIP

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Equitoxic Doses of 5-Azacytidine and 5-Aza-2′Deoxycytidine Induce Diverse Immediate and Overlapping Heritable Changes in the Transcriptome 英文参考文献.doc

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Equitoxic Doses of 5-Azacytidine and 5-Aza-2′Deoxycytidine Induce Diverse Immediate and Overlapping Heritable Changes in the Transcriptome 英文参考文献

EquitoxicDosesof5-Azacytidineand5-Aza- 29DeoxycytidineInduceDiverseImmediateand OverlappingHeritableChangesintheTranscriptome XiangningQiu1,4.,ChristofferHother2.,UlrikM.Ralfki?r2,AlexandraS?gaard2,QianjinLu4, ChristopherT.Workman3,GangningLiang1,PeterA.Jones1,KirstenGr?nb?k2* 1DepartmentofBiochemistryandMolecularBiology,UniversityofSouthernCalifornia/NorrisComprehensiveCancerCenter,KeckSchoolofMedicineoftheUniversityof Southern California, Los Angeles, California, United States of America, 2Department of Hematology, Rigshospitalet, Copenhagen, Denmark, 3Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark, 4Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China Abstract Background:Thehypomethylatingagent5-Azacytidine(5-Aza-CR)isthefirstdrugtoprolongoverallsurvivalinpatients withmyelodysplasticsyndrome(MDS).Surprisingly,thedeoxyribonucleosideanalog5-Aza-29deoxycytidine(5-Aza-CdR)did nothaveasimilareffectonsurvivalinalargeclinicaltrial.Bothdrugsarethoughttoexerttheireffectsafterincorporation intoDNAbycovalentbindingofDNAmethyltransferase(DNMT).While5-Aza-CdRisincorporatedintoonlyDNA,5-Aza-CR isalsoincorporatedintoRNA.Here,wehaveanalyzedwhetherthisdifferenceinnucleicacidincorporationmayinfluence thecapacitiesofthesedrugstoregulatetheexpressionofmRNAandmicroRNAs(miRNA),whichmaypotentiallyaffectthe activitiesofthedrugsinpatients. Methodology/Principal Findings: A hematopoietic (HL-60; acute myeloid leukemia) and a solid (T24; transitional cell carcinoma)cancercelllineweretreatedwithequitoxicdosesof5-Aza-CRand5-Aza-CdRfor24hrs,andtheimmediate(day 2)and lasting (day8) effectson RNA expression examined.There was considerable overlap between theRNAs heritably upregulatedbybothdrugsonday8butmoreRNAswerestablyinducedbythedeoxyanalog.Bothdrugsstronglyinduced expressionofcancertestisantigens.Onday2moreRNAsweredownregulatedby5-Aza-CR,particularlyathigherdoses.A remarkable downregulation of miRNAs and a