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Sequence-Specific DNA Binding by the NAC Coactivator Is Required for Potentiation of c-Jun-Dependent Transcription of the Osteocalcin Gene

Omar Akhouayri,¹ Isabelle Quélo,^1, and René St-Arnaud^1,2*

Genetics Unit, Shriners Hospital for Children, Montréal, Québec, Canada H3G 1A6,¹ Departments of Medicine, Surgery, and Human Genetics, McGill University, Montréal, Québec, Canada H3A 2T5²

Received 7 September 2004/ Returned for modification 14 October 2004/ Accepted 11 January 2005

Since the c-Jun coactivator NAC was initially identified in a differential screen for genes expressed in differentiated osteoblasts, we examined whether the osteocalcin gene, a specific marker of terminal osteoblastic differentiation, could be a natural target for the coactivating function of NAC. We had also previously shown that NAC can specifically bind DNA in vitro, but it remained unclear whether the DNA-binding function of NAC is expressed in vivo or if it is required for coactivation. We have identified an NAC binding site within the murine osteocalcin gene proximal promoter region and demonstrated that recombinant NAC or NAC from ROS17/2.8 nuclear extracts can specifically bind this element. Using transient transfection assays, we have shown that NAC specifically potentiated the c-Jun-dependent transcription of the osteocalcin promoter and that this activity specifically required the DNA-binding domain of NAC. Chromatin immunoprecipitation confirmed that NAC occupies its binding site on the osteocalcin promoter in living osteoblastic cells expressing osteocalcin. Inhibition of the expression of endogenous NAC in osteoblastic cells by use of RNA interference provoked a decrease in osteocalcin gene transcription. Our results show that the osteocalcin gene is a target for the NAC coactivating function, and we propose that NAC is specifically targeted to the osteocalcin promoter through its DNA-binding activity as a means to achieve increased specificity in gene transcription.

Present address: Aventis Pharma Deutschland GmbH, Industriepark Hoechst, D-65926 Frankfurt am Main, Germany.

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