An Unmethylated 3′ Promoter-Proximal Region Is Required for Efficient Transcription Initiation 英文参考文献.docVIP

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An Unmethylated 3′ Promoter-Proximal Region Is Required for Efficient Transcription Initiation 英文参考文献.doc

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An Unmethylated 3′ Promoter-Proximal Region Is Required for Efficient Transcription Initiation 英文参考文献

AnUnmethylated39Promoter-Proximal RegionIsRequiredforEfficient TranscriptionInitiation Ruth Appanah1[,David R.Dickerson2[¤,Preeti Goyal1,Mark Groudine2,3,Matthew C.Lorincz1* 1DepartmentofMedicalGenetics,TheUniversityofBritishColumbia,Vancouver,BritishColumbia,Canada,2DivisionofBasicSciences,FredHutchinsonCancerResearch Center, Seattle, Washington, United States of America, 3 Department of Radiation Oncology, University of Washington School of Medicine, Seattle, Washington, United StatesofAmerica Thepromoterregionsofapproximately40%ofgenesinthehumangenomeareembeddedinCpGislands,CpG-rich regionsthatfrequentlyextendontheorderofonekb39ofthetranscriptionstartsite(TSS)region.CpGs39oftheTSS ofactivelytranscribedCpGislandpromoterstypicallyremainmethylation-free,indicatingthatmaintainingpromoter- proximal CpGs in an unmethylated state may be important for efficient transcription. Here we utilize recombinase- mediated cassette exchange to introduce a Moloney Murine Leukemia Virus (MoMuLV)-based reporter, in vitro methylated1kbdownstream oftheTSS,intoadefinedgenomicsite.Inasubsetofclones,methylation spreadsto within ;320 bp of the TSS, yielding a dramatic decrease in transcript level, even though the promoter/TSS region remains unmethylated. Chromatin immunoprecipitation analyses reveal that such promoter-proximal methylation resultsinlossofRNApolymeraseIIandTATA-box-bindingprotein(TBP)bindinginthepromoterregion,suggesting thatrepressionoccursattheleveloftranscriptioninitiation.WhileDNAmethylation-dependenttrimethylationofH3 lysine(K)9isconfinedtotheintragenicmethylatedregion,thepromoteranddownstreamregionsarehypo-acetylated on H3K9/K14. Furthermore, DNase I hypersensitivity and methylase-based single promoter analysis (M-SPA) experiments reveal that a nucleosome is positioned over the unmethylated TATA-box in these clones, indicating thatdenseDNAmethylationdownstreamofthepromoterregionissufficienttoalterthechromatinstructureofan unmethylated promoter. Based on t