Ballas Nurit, Grunseich Christopher, Lu Diane D, Speh Joan C, Mandel Gail
Howard Hughes Medical Institute, Department of Neurobiology and Behavior, The State University of New York at Stony Brook, Stony Brook, New York 11794.
Howard Hughes Medical Institute, Department of Neurobiology and Behavior, The State University of New York at Stony Brook, Stony Brook, New York 11794.
Cell. 2005 May 20;121(4):645-657. doi: 10.1016/j.cell.2005.03.013.
Regulation of neuronal gene expression is critical to central nervous system development. Here, we show that REST regulates the transitions from pluripotent to neural stem/progenitor cell and from progenitor to mature neuron. In the transition to progenitor cell, REST is degraded to levels just sufficient to maintain neuronal gene chromatin in an inactive state that is nonetheless poised for expression. As progenitors differentiate into neurons, REST and its co-repressors dissociate from the RE1 site, triggering activation of neuronal genes. In some genes, the level of expression is adjusted further in neurons by CoREST/MeCP2 repressor complexes that remain bound to a site of methylated DNA distinct from the RE1 site. Expression profiling based on this mechanism indicates that REST defines a gene set subject to plasticity in mature neurons. Thus, a multistage repressor mechanism controls the orderly expression of genes during development while still permitting fine tuning in response to specific stimuli.
神经元基因表达的调控对中枢神经系统的发育至关重要。在此，我们表明REST调节从多能细胞向神经干/祖细胞以及从祖细胞向成熟神经元的转变。在向祖细胞的转变过程中，REST降解至刚好足以维持神经元基因染色质处于虽准备好表达但仍无活性状态的水平。随着祖细胞分化为神经元，REST及其共抑制因子从RE1位点解离，触发神经元基因的激活。在一些基因中，神经元中的表达水平通过仍与不同于RE1位点的甲基化DNA位点结合的CoREST/MeCP2抑制复合物进一步调节。基于此机制的表达谱分析表明，REST定义了一组在成熟神经元中具有可塑性的基因。因此，一种多阶段抑制机制在发育过程中控制基因的有序表达，同时仍允许根据特定刺激进行微调。
