Cell signaling switches HOX-PBX complexes from repressors to activators oftranscription mediated by histone deacetylases and histone acetyltransferases

The Hoxb1 autoregulatory element comprises three HOX-PBX binding sites. Des pite the presence of HOXB1 and PBX1, this enhancer fails to activate report er gene expression in retinoic acid-treated P19 cell monolayers. Activation requires cell aggregation in addition to RA. This suggests that HOX-PBX co mplexes may repress transcription under some conditions. Consistent with th is, multimerized HOX-PBX binding sites repress reporter gene expression in HEK293 cells. We provide a mechanistic basis for repressor function by demo nstrating that a corepressor complex, including histone deacetylases (HDACs ) 1 and 3, mSIN3B, and N-CoR/SMRT, interacts with PBX1A. We map a site of i nteraction with HDAC1 to the PBX1 N terminus and show that the PBX partner is required for repression by the HOX-PBX complex. Treatment with the deace tylase inhibitor trichostatin A not only relieves repression but also conve rts the HOX-PBX complex to a net activator of transcription. We show that t his activation function is mediated by the recruitment of the coactivator C REB-binding protein by the HOX partner. Interestingly, HOX-PBX complexes ar e switched from transcriptional repressors to activators in response to pro tein kinase A signaling or cell aggregation. Together, our results suggest a model whereby the HOX-PBX complex can act as a repressor or activator of transcription via association with corepressors and coactivators. The model implies that cell signaling is a direct determinant of HOX-PBX function in the patterning of the animal embryo.