Evidence for Transgenerational Transmission of Epigenetic Tumor Susceptibility in Drosophila 英文参考文献.docVIP

EvidenceforTransgenerationalTransmission ofEpigeneticTumorSusceptibility inDrosophila Yalan Xing1,Song Shi1,Long Le2,Crystal A.Lee1,Louise Silver-Morse1,Willis X.Li1* 1 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America, 2 Department of Medicine, University of RochesterMedicalCenter,Rochester,NewYork,UnitedStatesofAmerica Transgenerational epigenetic inheritance results from incomplete erasure of parental epigenetic marks during epigenetic reprogramming at fertilization. The significance of this phenomenon, and the mechanism by which it occurs,remainsobscure.Here,weshowthatgeneticmutations inDrosophila maycauseepigenetic alterations that, wheninherited, influence tumorsusceptibility oftheoffspring. Wefoundthatmanyofthemutations thataffected tumorigenesis induced by a hyperactive JAK kinase, HopTum-l, also modified the tumor phenotype epigenetically, suchthat themodification persisted even intheoffspring thatdidnotinherit themodifier mutation. Weanalyzed mutations of the transcription repressor Kru¨ppel (Kr), which is one of the hopTum-l enhancers known to affect ftz transcription. Wedemonstrate that the Krmutation causes increased DNAmethylation inthe ftzpromoter region, andthattheaberrant ftztranscription andpromoter methylation arebothtransgenerationally heritable ifHopTum-l ispresentintheoocyte. Theseresultssuggestthatgeneticmutations mayalterepigenetic markings intheformof DNA methylation, which are normally erased early in the next generation, and that JAK overactivation disrupts epigenetic reprogramming and allows inheritance of epimutations that influence tumorigenesis in future generations. Citation:XingY,ShiS,LeL,LeeCA,Silver-MorseL,etal.(2007)EvidencefortransgenerationaltransmissionofepigenetictumorsusceptibilityinDrosophila.PLoSGenet3(9): e151.doi:10.1371/journal.pgen.0030151 a variety of eukaryotic organisms ranging from plants to humans[15],theprecisemechanis