The epigenetic role of EGR1 during postnatal brain development and in neuronal activity

EGR1 在出生后大脑发育和神经元活动中的表观遗传作用

• 批准号: 9176391
• 负责人: Hehuang Xie
• 金额: $ 33.88万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176391
• 关键词: Binding; Binding Sites; Biological Assay; Biological Process; Birth; Brain; Cells; CpG dinucleotide; DNA; DNA Methylation; Data; Development; Enhancers; Enzymes; Epigenetic Process; Exhibits; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genomics; Growth; Histones; Human; In Vitro; Knockout Mice; Life Experience; Link; Mediating; Mediator of activation protein; Memory; Methods; Methylation; Modification; Molecular Profiling; Mus; Nervous system structure; Neuroglia; Neuronal Plasticity; Neurons; Nucleic Acid Regulatory Sequences; Play; Recruitment Activity; Regulation; Research Personnel; Role; Site; Stem cells; Synaptic plasticity; Testing; Tetanus Helper Peptide; Translations; Work; abstracting; base; brain shape; cell type; critical period; demethylation; epigenetic regulation; epigenomics; experience; frontal lobe; gene environment interaction; insight; loss of function; methylation pattern; methylome; mouse model; nerve stem cell; nervous system disorder; neural circuit; neuron development; newborn neuron; novel; overexpression; postnatal; practical application; programs; public health relevance; relating to nervous system; response; tool; transcription factor; transcriptome sequencing

TITLE: The epigenetic role of EGR1 during postnatal brain development and in neuronal activity Project Summary/Abstract Early growth response gene-1 (Egr1) is a critical transcription factor involved in many important biological processes, including neuronal plasticity and memory formation. With a rapid increase in expression during the first few weeks after birth, Egr1 controls the selection, maturation and functional integration of newborn neurons. The regulation of Egr1-mediated gene expression has been shown to be under methylation control. However, Egr1 target sites and their epigenetic regulation in the nervous system remains largely unknown. The investigators have recently identified a large number of genomic loci with their cell-type specific methylation patterns established during postnatal frontal cortex development. For both human and mouse, these loci enrich for transcription factor binding motifs, in particular for Egr1. The CpG dinucleotides within these predicted EGR1 binding sites become hypo-methylated in mature neurons but remain heavily methylated in glia. In this study, the investigators propose to systematically investigate Egr1-mediated epigenetic regulatory networks underlying the postnatal brain development. The central hypothesis is that, Egr1 is a key mediator for gene-environment interactions shaping brain methylome during early postnatal development, and plays an essential role in the establishment of cell-type specific DNA methylation patterns and in the epigenetic control of activity-induced methylation changes. In Aim 1, the investigators will determine the methylation profiles of EGR1 binding sites during postnatal brain development. In Aim 2, the investigators will determine DNA demethylation mechanism underlying the postnatal brain development. Gain- or loss-of-function methods will be used to manipulate Egr1 and Tet enzymes expression to test the hypothesis that increased Egr1 and Tet enzymes expression is prerequisites for the establishment of the cell-type specifically methylation patterns on its target sites during development. In addition, the investigators will examine whether high basal Egr1 expression is required to maintain the hypo-methylation states of its binding sites. Given the critical role of Egr1 in brain development and function, the investigators anticipate that these studies will provide important new insights into the key epigenetic mechanisms that underlie postnatal brain development and neuronal activity.

标题：EGFR 1在出生后脑发育和神经元活动中的表观遗传作用 项目总结/摘要 早期生长反应基因1（Early growth response gene-1，Egr 1）是一个重要的转录因子，参与许多重要的生物学过程。 过程，包括神经元可塑性和记忆形成。随着表达的快速增加， 出生后的最初几周，Egr 1控制新生儿的选择，成熟和功能整合 神经元Egr 1介导的基因表达的调节已被证明是甲基化控制下。 然而，Egr 1靶位点及其在神经系统中的表观遗传调控在很大程度上仍然未知。的 研究人员最近鉴定了大量具有细胞类型特异性甲基化的基因组位点 在出生后额叶皮层发育过程中形成的模式。对于人类和小鼠，这些基因座 富集转录因子结合基序，特别是Egr 1。其中的CpG二核苷酸 预测的EGFR 1结合位点在成熟神经元中变得低甲基化，但在神经元中保持高度甲基化 神经胶质。在这项研究中，研究人员建议系统地研究Egr 1介导的表观遗传调控， 出生后大脑发育的潜在网络。核心假设是，Egr 1是一个关键的调解人， 基因-环境相互作用在出生后早期发育过程中塑造了大脑甲基化组，并发挥了重要作用。 在建立细胞类型特异性DNA甲基化模式和表观遗传控制中的重要作用 活性诱导的甲基化变化。在目标1中，研究人员将确定 出生后大脑发育过程中的EGR 1结合位点。在目标2中，研究人员将确定DNA 去甲基化机制是脑发育的基础。功能获得或丧失方法将 用于操纵Egr 1和泰特酶表达，以检验Egr 1和泰特增加的假设 酶的表达是建立细胞类型特异性甲基化模式的先决条件， 在发展过程中的目标。此外，研究人员还将检查高基础Egr 1 表达是维持其结合位点的低甲基化状态所必需的。鉴于Egr 1的关键作用 在大脑发育和功能方面，研究人员预计，这些研究将提供重要的新信息， 深入了解出生后大脑发育和神经元活动的关键表观遗传机制。