Differential DNA Methylation Correlates with Differential Expression of Angiogenic Factors in Human Heart Failure 英文参考文献.docVIP

DifferentialDNAMethylationCorrelateswithDifferential ExpressionofAngiogenicFactorsinHumanHeartFailure MehreganMovassagh1,Mun-KitChoy1,MartinGoddard2,MartinR.Bennett1,ThomasA.Down3, RogerS.-Y.Foo1* 1Division of Cardiovascular Medicine, Addenbrooke’s Centre for Clinical Investigation, University of Cambridge, Cambridge, United Kingdom, 2Department of Histopathology,PapworthHospital,Cambridge,UnitedKingdom,3CancerResearchUKGurdonInstitute,UniversityofCambridge,Cambridge,UnitedKingdom Abstract Epigenetic mechanisms such as microRNA and histone modification are crucially responsible for dysregulated gene expression in heart failure. In contrast, the role of DNA methylation, another well-characterized epigenetic mark, is unknown.Inordertoexaminewhetherhumancardiomyopathyofdifferentetiologiesareconnectedbyaunifyingpattern of DNA methylation pattern, we undertook profiling with ischaemic and idiopathic end-stage cardiomyopathic left ventricular (LV) explants from patients who had undergone cardiac transplantation compared to normal control. We performed a preliminary analysis using methylated-DNA immunoprecipitation-chip (MeDIP-chip), validated differential methylationlocibybisulfite-(BS)PCRandhighthroughputsequencing,andidentified3angiogenesis-relatedgeneticloci that were differentially methylated. Using quantitative RT-PCR, we found that the expression of these genes differed significantly between CM hearts and normal control (p,0.01). Moreover, for each individual LV tissue, differential methylation showed a predicted correlation to differential expression of the corresponding gene. Thus, differential DNA methylationexistsinhumancardiomyopathy.InthisseriesofheterogenouscardiomyopathicLVexplants,differentialDNA methylation wasfoundin atleast3 angiogenesis-related genes. While inother systems,changes inDNA methylationat specific genomic loci usually precede changes in the expression of corresponding genes, our current findings in cardiomyopathymeritfurther investigatio