Telese Francesca, Ma Qi, Perez Patricia Montilla, Notani Dimple, Oh Soohwan, Li Wenbo, Comoletti Davide, Ohgi Kenneth A, Taylor Havilah, Rosenfeld Michael G
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Bioinformatis and System Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Neuron. 2015 May 6;86(3):696-710. doi: 10.1016/j.neuron.2015.03.033. Epub 2015 Apr 16.
One of the exceptional properties of the brain is its ability to acquire new knowledge through learning and to store that information through memory. The epigenetic mechanisms linking changes in neuronal transcriptional programs to behavioral plasticity remain largely unknown. Here, we identify the epigenetic signature of the neuronal enhancers required for transcriptional regulation of synaptic plasticity genes during memory formation, linking this to Reelin signaling. The binding of Reelin to its receptor, LRP8, triggers activation of this cohort of LRP8-Reelin-regulated neuronal (LRN) enhancers that serve as the ultimate convergence point of a novel synapse-to-nucleus pathway. Reelin simultaneously regulates NMDA-receptor transmission, which reciprocally permits the required γ-secretase-dependent cleavage of LRP8, revealing an unprecedented role for its intracellular domain in the regulation of synaptically generated signals. These results uncover an in vivo enhancer code serving as a critical molecular component of cognition and relevant to psychiatric disorders linked to defects in Reelin signaling.
大脑的一个特殊特性是其通过学习获取新知识并通过记忆存储该信息的能力。将神经元转录程序的变化与行为可塑性联系起来的表观遗传机制在很大程度上仍然未知。在这里，我们确定了记忆形成过程中突触可塑性基因转录调控所需的神经元增强子的表观遗传特征，并将其与Reelin信号传导联系起来。Reelin与其受体LRP8的结合触发了这一组由LRP8-Reelin调节的神经元（LRN）增强子的激活，这些增强子是一条新的突触到细胞核途径的最终汇聚点。Reelin同时调节NMDA受体传递，这反过来又允许所需的γ-分泌酶依赖性LRP8切割，揭示了其细胞内结构域在调节突触产生的信号方面前所未有的作用。这些结果揭示了一种体内增强子编码，它是认知的关键分子成分，并且与与Reelin信号缺陷相关的精神疾病有关。
