The Effect Of HDAC1 And Acetylated HDAC1 On Corepressor Complex Activity And Hematopoiesis

Histone deacetylases(HDACs) play important roles in the transcriptional regulation of eukaryotic genes.Several lines of evidence also link HDACs to cancer.HDAC1 and HDAC2 are highly conserved enzymes and are present in repressor complexes.We previously reported that glucocorticoid receptor(GR) associated HDAC1 is gradually acetylated by p300 during the GR mediated transcription cycle,which lead to loss of its deacetylase activity.Here we showed that HDAC2 is also required for GR mediated gene activation.But HDAC2 is not acetylated by p300,although 5 out of 6 acetylated lysine residues in HDAC1 are also present in HDAC2.More importantly,the activity of HDAC2 is inhibited by acetylated HDAC1.Additionally,we showed that HDAC1 and 2 can trans-regulate through hetero-dimerizition.Thus,this study uncovered fundamental differences between HDAC1 and 2.In addition,understanding the structure and functional differences between HDAC1 and HDAC2 might shed light on new strategies for developing isoform specific HDACs inhibitors for the treatment of leukemia and other cancers.HDAC1 has been shown to interact with many key hematopoiesis transcription fators and to influence their activities.Our data showed that during erythroid differentiation,although HDAC1 remains bound to GATA1,its associated deacetylase activity significantly decreased.Meanwhile,HDAC1 acetylation level is significantly increased.The overexpression of HDAC1 can promote erythroid cell proliferation and inhibits induced differentiation,the knockdown of HDAC1 or 2 inhibits erythroid cell proliferation and promotes induced differentiation.We also found that HDAC1 affects GATA1 mediated transcription activity.Thus our data revealed that HDAC1 may negatively regulate GATA1 mediated transcription and suggest that the dynamic regulation of GATA1 associated NuRD/MeCP1/HDAC1/HDAC2 complex may determine the onset of erythroid differentiation programs.Moreover,this study will eventually help to design new therapeutic approaches in treatment of leukemia.