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: 10427296
• 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/10427296
• 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.

摘要 经验是由海马体中一小群被招募的神经元编码的。虽然多个 当神经元接受刺激时，只有一部分神经元被“分配”来编码给定的记忆。已经 表明具有较高内在兴奋性的神经元在情境中优先被募集， 暴露，但神经元募集的原则尚不清楚。神经元分配具有医疗 相关性，因为它是记忆形成的第一步，因此可以有针对性地减轻认知缺陷 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的分配， 海马体。具体来说，我们发现了数千个小的基因组区域，这些区域存在于某些细胞中， 完全甲基化，在其他情况下，完全未甲基化的状态，与周围的基因组相反， 在所有神经元中都是均匀甲基化或非甲基化的。由于这些区域嵌入突触中 基因并具有DNA甲基化依赖的转录增强效应，它们可以被概念化。 作为调节神经元/突触活性的基于DNA甲基化的β-内酰胺酶增强剂。我们建议 鉴定的神经元增强子在“甲基化”和“非甲基化”位置之间交替， 这在任何给定的时间提供了小的（稀疏的）但足够的具有特异性的神经元群体， 未甲基化和甲基化开关的星座，其有资格分配给编码体验。 本申请的目的是测试鉴定的表观遗传学上的DNA序列在以下方面的作用： 神经元分配我们将1）通过对以下基因的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）测试神经增强子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诱导的认知变化 功能我们的模型的前提是，它提供了，通过表观遗传开关，一个组合- 神经元分配和稀疏/分离群体编码的难以捉摸过程的分子机制 经验的。此外，基于DNA甲基化的开关的敏感性提供了机会， 他们的选择性操纵，以改善神经元的分配和编码在认知障碍。