Department of Biochemistry and Molecular Biology, McCormick Genomic and Proteomic Center, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA.
Mol Cell. 2013 Feb 21;49(4):704-18. doi: 10.1016/j.molcel.2012.12.016. Epub 2013 Jan 24.
ATP-dependent NuRD repressor complexes involve combinatorial assembly of its subunits. However, the mechanism of gene transcription by MTA1/NuRD remains enigmatic. Here we report that MTA1 methylation by G9a methytransferase and demethylation by LSD1 determines the nucleosome remodeling and transcriptional outcome. Contrary to the current static repressor model of the NuRD complex, we discovered that MTA1 association with nucleosomes and corepressor/coactivator complexes is dynamic. While methylated MTA1 is required for the NuRD repressor complex, demethylated MTA1 recognizes the bivalent histone H3K4-AcK9 mark and recruits coactivator NURF-trithorax remodeling complex in a signaling-dependent manner. MTA1's lysine 532 methylation represents a molecular switch as methylated and demethylated MTA1 nucleate NuRD or NURF complexes with opposite functions in a cyclical manner. In addition, MTA1 possesses an inherent histone amplifier activity with an instructive role in impacting the epigenetic landscape, providing a new perspective to the molecular governance of dual coregulator functions of a master coregulator.
ATP 依赖性 NuRD 抑制复合物涉及其亚基的组合装配。然而，MTA1/NuRD 介导的基因转录机制仍然是一个谜。在这里，我们报告说，G9a 甲基转移酶对 MTA1 的甲基化和 LSD1 的去甲基化决定了核小体重塑和转录结果。与 NuRD 复合物的当前静态抑制模型相反，我们发现 MTA1 与核小体和核心抑制物/共激活物复合物的结合是动态的。虽然甲基化的 MTA1 是 NuRD 抑制复合物所必需的，但去甲基化的 MTA1 识别二价组蛋白 H3K4-AcK9 标记，并以信号依赖性方式募集共激活剂 NURF-trithorax 重塑复合物。MTA1 的赖氨酸 532 甲基化代表了一个分子开关，因为甲基化和去甲基化的 MTA1 以循环方式引发 NuRD 或 NURF 复合物，具有相反的功能。此外，MTA1 具有内在的组蛋白扩增活性，在影响表观遗传景观方面具有指导作用，为主要共激活因子的双重共激活因子功能的分子调控提供了新的视角。
