Histone deacetylase 3 (HDAC3) is recruited to target promoters by PML-RARα as a component of the N-CoR co-repressor complex to repress transcription in vivo

PML-RAR alpha is a chimeric transcription factor tightly associated with acute promyelocytic leukemia. PML-RAR alpha plays an important role in the aberrant transcription repression on the target genes of wild-type retinoic acid receptors. Here, we demonstrated that HDAC3, one component of the N-CoR transcription repressor complex, is a key regulator of the transcription repression by PML-RARa in vivo. Using immunoprecipitation, we demonstrated that PML-RAR alpha interacts with N-CoR/HDAC3 in vivo without ligand. Next, using chromatin immunoprecipitation (ChIP) assay, this N-CoR/HDAC3 co-repressor complex was recruited to the endogenous target promoters (RAR beta and CYP26) through PML-RAR alpha. The neighboring histones were de-acetylated and gene expression was repressed. When HDAC3 protein was knocked down by RNA interference in PML-RAR alpha-expressing cells, the endogenous target genes were significantly activated, which was also confirmed by promoter-luciferase reporter assay. These results provide evidence to show that the N-CoR/HDAC3 co-repressor complex is involved in the aberrant transcription regulation in PM L-RAR alpha-expressing cells. (c) 2006 Elsevier Inc. All rights reserved.