Drosophila Histone Deacetylase-3 Controls Imaginal Disc Size through Suppression of Apoptosis 英文参考文献.docVIP

DrosophilaHistoneDeacetylase-3ControlsImaginalDisc SizethroughSuppressionofApoptosis ChangqiC.Zhu1,2.,DouglasJ.Bornemann1,2.,DavidZhitomirsky1,2,EllenL.Miller1,MichaelB. O’Connor1,2,JeffreyA.Simon1* 1DepartmentofGenetics,CellBiologyandDevelopment,UniversityofMinnesota,Minneapolis,Minnesota,UnitedStatesofAmerica,2HowardHughesMedicalInstitute, ChevyChase,Maryland,UnitedStatesofAmerica Abstract Histonedeacetylases(HDACs)executebiologicalregulationthroughpost-translationalmodificationofchromatinandother cellular substrates. In humans, there are eleven HDACs, organized into three distinct subfamilies. This large number of HDACsraisesquestionsaboutfunctionaloverlapanddivisionoflaboramongparalogs.Invivorolesaresimplertoaddress inDrosophila,wherethereareonlyfiveHDACfamilymembersandonlytwoareimplicatedintranscriptionalcontrol.Of these two, HDAC1 has been characterized genetically, but its most closely related paralog, HDAC3, has not. Here we describetheisolationandphenotypiccharacterizationofhdac3mutations.Wefindthatbothhdac3andhdac1mutations are dominant suppressors of position effect variegation, suggesting functional overlap in heterochromatin regulation. However, all five hdac3 loss-of-function alleles are recessive lethal during larval/pupal stages, indicating that HDAC3 is essential on its own for Drosophila development. The mutant larvae display small imaginal discs, which result from abnormally elevated levels of apoptosis. This cell death occurs as a cell-autonomous response to HDAC3 loss and is accompanied by increased expression of the pro-apoptotic gene, hid. In contrast, although HDAC1 mutants also display smallimaginaldiscs,thisappearstoresultfromreducedproliferationratherthanfromelevatedapoptosis.Theconnection betweenHDAClossandapoptosisisimportantsinceHDACinhibitorsshowanticanceractivitiesinanimalmodelsthrough mechanisms involving apoptotic induction. However, the specific HDACs implicated in tumor cell killing have not been identified. Our results indicate