DNA methylation based binary enhancers govern neuronal allocation to coding in the hippocampus

摘要 经验是由海马体中新招募的神经元的小集合编码的。尽管有多个 神经元接受刺激，只有其中的一部分被“分配”给给定的记忆编码。一直以来 结果表明，具有更高水平的内在兴奋性的神经元在语境中优先被招募 然而，管理神经元招募的原则尚不清楚。神经元分配具有医学意义 相关性，因为它是记忆形成的第一步，因此可能旨在缓解认知缺陷 与衰老、阿尔茨海默病和其他神经退行性疾病有关。在这里，我们介绍一个 模型，通过基于DNA甲基化的二元增强子可以解释神经元在 海马体。具体地说，我们确定了数千个存在于某些细胞中的小基因组区域 完全甲基化的，在其他情况下，处于完全未甲基化的状态，与周围的基因组形成对比，这 在所有神经元中均为甲基化或非甲基化。因为这些区域嵌入在突触中 基因，并具有依赖DNA甲基化的转录增强效应，它们可以被概念化 作为基于DNA甲基化的双稳态增强剂，调节神经元/突触的活动。我们建议， 已识别的神经元增强剂在“甲基化”和“非甲基化”位置之间交替，并且 这在任何给定的时间都提供了一个小的(稀疏的)但足够的神经元群体，具有特定的 有资格分配给代码体验的未甲基化和甲基化开关的星座。 此应用程序的目标是测试已识别的表观遗传双稳DNA序列在 神经元分配。我们将1)通过对甲基组进行测序来确定分配表观遗传密码 分配的神经元，2)测试双稳态增强剂和神经元分配之间的功能联系，以及3) 评估增强剂的表观遗传延展性是否有助于环境诱导的认知变化 功能正常。我们模型的前提是，通过表观遗传转换，它提供了一种组合- 难以捉摸的神经元分配和稀疏/分离群体编码过程的分子机制 体验。此外，基于DNA甲基化的开关的敏感性提供了一个机会 他们的选择性操作，以改善认知障碍的神经元分配和编码。

Abstract Experiences are coded by small ensembles of recruited neurons in the hippocampus. Although multiple neurons receive a stimulus, only a subset of them is “allocated” to encode a given memory. It has been shown that neurons with higher levels of intrinsic excitability are preferentially recruited during context exposure, yet the principles governing neuron recruitment are not known. Neuron allocation has medical relevance, as it is the first step in memory formation and thus may be targeted to mitigate cognitive deficits associated with aging and Alzheimer's disease and other neurodegenerative disorders. Here we introduce a model that, via DNA methylation based binary enhancers may explain neuron allocation in the hippocampus. Specifically, we identified thousands of small genomic regions that in some cells exist in fully methylated, and in others, in fully unmethylated states, in contrast to the surrounding genome, which is uniformly methylated or unmethylated in all neurons. Since these regions are embedded in synaptic genes and have a DNA methylation dependent transcription-enhancing effect, they can be conceptualized as DNA methylation based bistable enhancers regulating neuronal/synaptic activity. We propose that the identified neuronal enhancers alternate between the “methylated” and “unmethylated” positions, and that this provides, at any given time, a small (sparse) but sufficient population of neurons with specific constellations of unmethylated and methylated switches that is eligible for allocation to code experiences. The goal of this application is to test the role of the identified epigenetically bistable DNA sequences in neuron allocation. We will 1) determine the allocation epigenetic code by sequencing the methylome of allocated neurons, 2) test the functional link between bistable enhancers and neuron allocation, and 3) assess if epigenetic malleability of enhancers contributes to environment-induced changes in cognitive functioning. The premise of our model is that it provides, through epigenetic switching, a combinatorial- molecular mechanism for the elusive process of neuron allocation and sparse/segregated population coding of experiences. Furthermore, the sensitivity of DNA methylation based switches provides an opportunity for their selective manipulation to improve neuron allocation and encoding in cognitive disorders.