Nuclear Hormone Orphan Receptor Rev-erb¦Â Apolipoprotein Apociii Transcriptional Regulatory Mechanisms

The family of the nuclear receptors(NRs)consists of transcription factors that regulate many important biological processes including homeostasis,differentiation,embryonic development,and organ physiology.NRs have also been implicated in various diseases,such as cancer,diabetes,and osteoporosis.The Rev-erbβis an orphan receptor and has been described as negative transcriptional regulators for many targets,such as N-myc.It was reported that the interactions of Rev-erbβwith corepressor,N-CoR,was dependent on an intact putative ligand binding domain and could enhance transcriptional repression of the orphan receptors.It was also found that the knockdown of histone deacetylase 3(HDAC3),a component in the N-CoR-containing complex,markedly increased the expression of Bmall mRNA.Despite extensive research,it is still not clear how the transcriptional repression mediated by both of Rev-erba and Rev-erβis relieved.In this study,Rev-erbβwas found could bind apoCIII promoter ans repress its activity.In yeast two-hybrid screen,Rev-erbβwas shown to bind with Tat-interactive protein 60kDa(Tip60), Histone deacetylase 1(HDAC1),Zn finger Hit domain contain protein-1(ZNHIT-1).The interaction Was further verified both by co-immunoprecipitation assay in vitro and GST pull down assay in vivo.We provided evidence that Tip60 directly acetylated the Rev-erbβresulting in relief of the repression of Rev-erbβto apoCⅢ.Substitution mutation established an important role for RXKK motif in acetylation of Rev-erbβand the Tip60-mediated relief of transcription repression activity of Rev-erbβ.ZNHIT-1 could bind Tip60 directly and maybe recruit Tip60 complex to regulate Rev-erbl3 function.Tip60-mediated relief of Rev-erbβtranscription repression was abrogated by increasing amounts of the HDAC1,suggesting that HDAC1 potentially function through direct deacetylation of Rev-erbβ.ZNHIT-1 also could bind Tip60,suggesting that ZNHIT-1 could affect Rev-erbβthrough recruiting other coactivators.The present study underlines the acetylation and potential deacetylation of the Rev-erbβis an important mechanism for regulating transcriptional activity.Thus we can understand how Rev-erbβis regulated by acetylation even without knowing the identity of the receptor's ligand.