Multiple coregulatory control of tyrosine hydroxylase gene transcription.

Despite ubiquitous expression and a high level of metastasis-associated protein 1 (MTA1) coregulator, the physiological role of the MTA1 coactivator remains unknown. We found that MTA1 is a bona fide coactivator and stimulator of tyrosine hydroxylase (TH) transcription in neuronal cells and that MTA1-null mice had lower TH expression in the striatum and substantial nigra. MTA1 physically achieves these functions by interacting directly with DJ1 (Parkinson disease 7) and in turn recruits the DJ1/MTA1/RNA polymerase II complex to the bicoid binding element (BBE) in the TH promoter. Furthermore, we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3. These findings reveal a role for MTA1 as an upstream coactivator of TH and advance the notion of polygenic regulation of a disease-causing gene by coordinated interactions of three regulatory proteins.