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

基于 DNA 甲基化的二元增强子控制海马体编码的神经元分配

• 批准号: 10191058
• 负责人: Miklos Toth
• 金额: $ 36.97万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191058
• 关键词: Aging; Alleles; Alzheimer' s Disease; Behavior; CREB1 gene; Cells; Code; Cognition Disorders; Cognitive; Cognitive deficits; DNA Methylation; DNA Sequence; Digit structure; Discrimination; Electrophysiology (science); Eligibility Determination; Enhancers; Environment; Epigenetic Process; Episodic memory; Equilibrium; Exhibits; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomic Segment; Goals; Hippocampus (Brain); Hormones; Image; Individual; Intrinsic factor; Link; Medical; Memory; Memory impairment; Methylation; Modeling; Molecular; Neurodegenerative Disorders; Neurons; Neurotransmitters; Paracrine Communication; Pattern; Population; Positioning Attribute; Process; Rest; Role; Slice; Stimulus; Synapses; Testing; Time; Work; age related; base; cognitive function; combinatorial; experience; improved; methylome; neuronal excitability; novel; recruit; synaptic function; transcription factor; way finding

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.

抽象的 经验是由海马体中招募的神经元的小群编码的，尽管有多个神经元。 神经元收到刺激后，只有其中的一部分被“分配”来编码给定的记忆。 研究表明，具有较高内在兴奋性的神经元在情境中会被优先招募 暴露，但控制神经元招募的原理尚不清楚。 相关性，因为它是记忆形成的第一步，因此可能旨在减轻认知缺陷 与衰老和阿尔茨海默氏病以及其他神经退行性疾病有关。 该模型通过基于 DNA 甲基化的二元增强子可以解释神经元分配 具体来说，我们发现了一些细胞中存在的数千个小基因组区域。 完全甲基化，而在其他情况下，处于完全非甲基化状态，与周围的基因组形成鲜明对比， 由于这些区域嵌入在突触中，因此在所有神经元中均一致甲基化或未甲基化。 基因并具有 DNA 甲基化依赖性转录增强作用，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/突触活动。 确定的神经增强子在“甲基化”和“非甲基化”位置之间交替，并且 这在任何给定时间提供了少量（稀疏）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非甲基化和甲基化开关的星座。 本应用的目的是测试已识别的表观遗传双稳态 DNA 序列在 我们将1）通过对甲基化组进行测序来确定分配表观遗传密码。 分配的神经元，2) 测试双稳态增强器和神经元分配之间的功能联系，以及 3) 评估增强子的表观遗传可塑性是否有助于环境引起的认知变化 我们模型的前提是它通过表观遗传转换提供了一种组合。 神经元分配和稀疏/隔离群体编码的难以捉摸过程的分子机制 此外，基于 DNA 甲基化的开关的敏感性提供了机会。 表彰他们的选择性操作，以改善认知障碍的神经分配和编码。