MYST Family Acetyltransferase HBO1 Regulates Histone Short-chain Hydrophobic Acylation

Histone proteins are subject to a wide range of post-translational modifications(PTMs),for example methylation,acetylation,phosphorylation etc.which alone or in combination,shape the chromatin states and function.Misregulation of histone PTMs has been intimately linked with a number of diseases,which include developmental and neurological disorders as well as various aetiologies of cancer.Recent studies indicate that histones are subjected to various types of acylation including acetylation,propionylation,butyrylation and crotonylation.p300/CBP(CREB-binding protein)have been shown to catalyze multiple types of acylation.In addition,MOF(also known as KAT8)also has been shown to possess histone acetylation,propionylation and crotonylation activity.However,whether HBO1(Histone acetyltransferase KAT7),a member of MYST family acetyltransferases,also catalyzes histone acylation beyond acetylation is currently unknown.Here,we show that HBO1 is also a versatile histone acyltransferase,with ability to catalyze histone acetylation,propionylation,butyrylation and crotonylation both in vivo and in vitro.Knockdown or knockout of HBO1 in various cell lines resulted in a dramatical decrease of not only histone acetylation but also histone propionylation,butyrylation and crotonylation.The HBO1 acyltransferase activity is dependent on HBO1's association with the JADE1(PHF17)or BRPF2(bromodomain-containing protein 1 BRD1),the known subunits of HBO1 acetyltransferase complexes.In support of this notion,knockdown of JADE1 or BRPF2 also led to global reduction of histone acylation.We also compared the effect of CBP knockdown with that of HBO1 knockdown and/or knockout on histone acetylation,and our results reveal that these two enzymes act independently and govern histone acylation at overlapping as well as distinct sites.Finally,we carried out genome-wide chromatin immunoprecipitation assay(Ch IP-seq)and gene expression profiling by RNA-seq and our results support a role of HBO1 in promoting gene transcription by catalyzing histone acylation at gene promoter region.