Expression of Linear and Novel Circular Forms of an INK4ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk 英文参考文献.docVIP

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Expression of Linear and Novel Circular Forms of an INK4ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk 英文参考文献.doc

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Expression of Linear and Novel Circular Forms of an INK4ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk 英文参考文献

ExpressionofLinearandNovelCircularFormsofan INK4/ARF-AssociatedNon-CodingRNACorrelateswith AtherosclerosisRisk ChristinE.Burd1,WilliamR.Jeck2,YanLiu2,HannaK.Sanoff3,ZefengWang4,NormanE.Sharpless1,2,5* 1TheCurriculuminToxicology,TheLinebergerComprehensiveCancerCenter,TheUniversityofNorthCarolinaSchoolofMedicine,ChapelHill,NorthCarolina,United StatesofAmerica,2DepartmentofGenetics,TheUniversityofNorthCarolinaSchoolofMedicine,ChapelHill,NorthCarolina,UnitedStatesofAmerica,3TheDivisionof Hematology and Oncology, University of Virginia, Charlottesville, Virginia, United States of America, 4Department of Pharmacology, The University of North Carolina SchoolofMedicine,ChapelHill,NorthCarolina,UnitedStatesofAmerica,5DepartmentofMedicine,TheUniversityofNorthCarolinaSchoolofMedicine,ChapelHill, NorthCarolina,UnitedStatesofAmerica Abstract Humangenome-wideassociationstudieshavelinkedsinglenucleotidepolymorphisms(SNPs)onchromosome9p21.3near theINK4/ARF(CDKN2a/b)locuswithsusceptibilitytoatheroscleroticvasculardisease(ASVD).Althoughthislocusencodes threewell-characterizedtumorsuppressors,p16INK4a,p15INK4b,andARF,theSNPsmoststronglyassociatedwithASVDare ,120kb from the nearest coding gene within a long non-coding RNA (ncRNA) known as ANRIL (CDKN2BAS). While individuals homozygous for the atherosclerotic risk allele show decreased expression of ANRIL and the coding INK4/ARF transcripts,themechanismbywhichsuchdistantgeneticvariantsinfluenceINK4/ARFexpressionisunknown.Here,using rapid amplification of cDNA ends (RACE) and analysis of next-generation RNA sequencing datasets, we determined the structureandabundanceofmultipleANRILspecies.Eachofthesespecieswaspresentatverylowcopynumbersinprimary and cultured cells; however, only the expression of ANRIL isoforms containing exons proximal to the INK4/ARF locus correlated with the ASVD risk alleles. Surprisingly, RACE also identified transcripts containing non-colinear ANRIL exonic sequences, whose expression also correlated with genot