The Roles Of SUMO Modification In Control Of Global Gene Expression And Histone Acetylation

Transcriptional regulation plays fundamental and vital roles in cellular gene expression.Previous studies indicate that MYC can amplify global gene transcription and that sumoylation broadly correlates with transcriptional repression.However,the underlying mechanisms for SUMO-mediated repression are not clear.Here,we demonstrate that SUMO can repress global transcription by CDK9 sumoylation.Furthermore,by generating a sumoylation-resistant CDK9 mutant CDK9KO/Myc-CDK9K/R cell line(all the twenty-nine lysine residues were mutated to arginine residues),we demonstrate that SUMO inhibits global transcription primarily through CDK9 sumoylation.On the other hand,we show that MYC amplifies global transcription mainly via antagonizing CDK9 sumoylation.Mechanistic studies indicate that CDK9 sumoylation blocks its interaction with Cyclin T1,thus,affects the formation of P-TEFb complex.We also show that MYC antagonizes CDK9 sumoylation possibly by competition for binding of enzymes involved in sumoylation.In addition,we also demonstrate that this discovery may play very important roles in regulation of cardiac hypertrophy development and T cell activation.Our previous studies indicate that multiple PIAS family proteins have capacity to repress global transcription without an effect on global histone acetylation when co-expressed with SUMO-1.Interestingly,we observed that among all PIAS family proteins,only PIASx? can repress both global transcription and histone acetylation.This global repression activity is sumoylation dependent,as it was not observed by E3 ligase activity-deficient PIASx? mutant.We show that the decreased histone acetylation mediated by PIASx? was neither due to histone H3 and H4 sumoylation nor to the inhibition of p300 acetyltransferase activity.Instead,we provide evidence that PIASx? specifically catalyze HDAC1/2 sumoylation and that HDAC1/2 sumoylation not only promotes its protein stability but also facilitate its binding to chromatin,thereby enhancing its histone deacetylase activity.Furthermore,we observed that over-expression of PIASx? correlates nicely with histone hypoacetylation in renal carcinoma tissues.Taken together,our study provides novel insights into the regulatory mechanisms by which sumoylation controls transcription and histone acetylation.