The Role Of SUMO Modification In Control Of Histone Acetylation And Histone Methylation

SUMO modification is one of the conserved protein post-translational modifications and plays a key role in many biological processes,including cell cycle,transcriptional regulation,chromatin remodeling,stem cell pluripotency and differentiation,DNA repair and ribosomal biosynthesis.Sumoylation may alters the conformation,binding,localization or stability of the substrate proteins.Previous studies have shown a striking correlation between sumoylation and transcription repression.The post-translational modifications of histone,especially histone acetylation and histone methylation,are thought to be a major factor in regulating transcription.Our study focuses on the cross-talk between SUMO modification and histone acetylation and histone methylation.Our previous studies showed that PIASx?-mediated HDAC1/2 sumoylation dramatically enhanced its histone deacetylase activity,resulting in its decreased histone acetylation.We further confirmed by Ch IP-Seq that SUMO modification promotes HDAC1/2 histone deacetylase activity.RNA-Seq results also showed that sumoylation of HDAC1/2 repressed transcription.According to the previous reports,we constructed sumoylation deficient mutants of HDAC1/2(HDAC1 K444R/K476 R,HDAC2 K462R).Sumoylation mutants of HDAC1/2 did not change their subcellular localization and the formation of HDAC1/2 containing complexes.However,the HDAC1/2-sumoylation mutants exhibited a decreased protein stability and reduced binding of chromatin,thus leading to impaired histone deacetylase activity.It was reported that HDAC1 can be deSUMOylated in vivo by SENP1.However,it is not clear that which SENP affects histone deacetylase activity of HDAC1/2 in vivo.Through exogenous over-expression of all SENPs(SENP1-7),we found that SENP6 but not other SENPs can significantly increase the cellular level of histone acetylation.The effect on histone acetylation is dependent on desumoylation activity of SENP6.Moreover,HDAC1 and HDAC2 can be deSUMOylated by SENP6.SENP6 not only decreases the protein stability of HDAC1/2 but also inhibits its binding to chromatin.In addition,SENP6 inhibited the proliferation of 293 T cells.Our study reveals a key role of SENP6 in regulation of HDAC1/2 histone deacetylase activity and provides a new insight into cross-talk between SUMOylation and histone acetylation.Mass spectrometry results revealed that many histone methyltransferases(HMTs)and histone demethylase(HDMs)are substrates of sumoylation.Currently,how SUMO modification regulates histone methylation is not yet clear.We found that expression of UBC9 and SUMO-1 specifically increased the level of H3K4me3.While knocking down of UBC9 specifically inhibited H3K4me3.We further showed that WDR5,a common subunit of the H3K4me3 methyltransferase MLL/SET1 complexes,was a sumoylation substrate.The cellular Sumoylation level did not affect WDR5's transcriptional level but inhibit its degradation.The detailed mechanism needs to to be further studied.However,current results suggest that SUMO modification may affect histone methylation through protein stability regulation.