Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, George Washington University Medical Center, Washington, DC 20037, USA.
Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4200-5. doi: 10.1073/pnas.1101193108. Epub 2011 Feb 22.
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.
尽管普遍表达和高水平的转移相关蛋白 1（MTA1）共调节剂，但 MTA1 共激活剂的生理作用仍然未知。我们发现 MTA1 是神经元细胞中酪氨酸羟化酶（TH）转录的真正共激活剂和刺激剂，而 MTA1 缺失小鼠在纹状体和黑质中有较低的 TH 表达。MTA1 通过与 DJ1（帕金森病 7）直接相互作用并依次招募 DJ1/MTA1/RNA 聚合酶 II 复合物到 TH 启动子中的双皮质结合元件（BBE）来实现这些功能。此外，我们发现 MTA1/DJ1 复合物是配对样同源域转录因子（Pitx3）同源域转录因子最佳刺激 TH 表达所必需的，并且 MTA1/DJ1 复合物通过 MTA1 与 Pitx3 的直接相互作用被募集到 TH 基因染色质上。这些发现揭示了 MTA1 作为 TH 的上游共激活剂的作用，并提出了由三个调节蛋白的协调相互作用导致疾病基因的多基因调节的概念。
