Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Neuron. 2011 Oct 6;72(1):72-85. doi: 10.1016/j.neuron.2011.08.022.
Autism spectrum disorders such as Rett syndrome (RTT) have been hypothesized to arise from defects in experience-dependent synapse maturation. RTT is caused by mutations in MECP2, a nuclear protein that becomes phosphorylated at S421 in response to neuronal activation. We show here that disruption of MeCP2 S421 phosphorylation in vivo results in defects in synapse development and behavior, implicating activity-dependent regulation of MeCP2 in brain development and RTT. We investigated the mechanism by which S421 phosphorylation regulates MeCP2 function and show by chromatin immunoprecipitation-sequencing that this modification occurs on MeCP2 bound across the genome. The phosphorylation of MeCP2 S421 appears not to regulate the expression of specific genes; rather, MeCP2 functions as a histone-like factor whose phosphorylation may facilitate a genome-wide response of chromatin to neuronal activity during nervous system development. We propose that RTT results in part from a loss of this experience-dependent chromatin remodeling.
自闭症谱系障碍，如雷特综合征（RTT），被认为是由于经验依赖性突触成熟缺陷引起的。RTT 是由 MECP2 基因突变引起的，MECP2 是一种核蛋白，在神经元激活时会在 S421 处发生磷酸化。我们在这里表明，体内破坏 MeCP2 S421 磷酸化会导致突触发育和行为缺陷，表明 MeCP2 的活性依赖性调节在大脑发育和 RTT 中起作用。我们研究了 S421 磷酸化调节 MeCP2 功能的机制，并通过染色质免疫沉淀测序表明，这种修饰发生在 MeCP2 跨越基因组结合的位置。MeCP2 S421 的磷酸化似乎不会调节特定基因的表达；相反，MeCP2 作为一种组蛋白样因子发挥作用，其磷酸化可能有助于在神经系统发育过程中，神经元活动引起的染色质的全基因组反应。我们提出，RTT 部分是由于这种经验依赖性染色质重塑的丧失所致。
