The epigenetic mechanism of enhancer RNA in behavioral plasticity

增强子RNA在行为可塑性中的表观遗传机制

• 批准号: 8893181
• 负责人: Tae-Kyung Kim
• 金额: $ 34.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893181
• 关键词: Accounting; Adverse effects; Architecture; Autistic Disorder; Behavior; Behavioral; Binding; Biochemical; Biological Assay; Biological Models; Brain; Cell Nucleus; Cells; Co-Immunoprecipitations; Code; Cognitive; Complex; Development; Elongation Factor; Enhancers; Epigenetic Process; Epilepsy; Exhibits; FOS gene; Fluorescent in Situ Hybridization; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genetic study; Health; High-Throughput Nucleotide Sequencing; Hippocampus (Brain); Human; Human Genetics; Immediate-Early Genes; Individual; Label; Learning; Link; Long-Term Potentiation; Maintenance; Mass Spectrum Analysis; Memory; Messenger RNA; Modeling; Molecular; Mutation; Names; Nature; Neurons; Neurophysiology - biologic function; Pathway interactions; Phase; Play; Production; Proteins; RNA; RNA Polymerase II; RNA Sequences; RNA chemical synthesis; Regulation; Rett Syndrome; Role; Rubinstein-Taybi Syndrome; Sensory; Signal Pathway; Signal Transduction; Slice; Source; Stimulus; Synapses; Synaptic plasticity; Testing; Translating; Untranslated RNA; Ursidae Family; base; clinically significant; cognitive function; conditioned fear; experience; genome-wide; genome-wide analysis; insight; interdisciplinary approach; long term memory; mRNA Expression; mammalian genome; memory consolidation; memory process; negative elongation factor; nervous system disorder; neural circuit; neuroregulation; novel; overexpression; programs; promoter; relating to nervous system; research study; response; spatiotemporal; transcriptome sequencing

DESCRIPTION (provided by applicant): A substantial body of evidence suggests that many neurological diseases may commonly result from perturbations of activity-dependent changes in neural functions. During brain development, sensory stimulation-dependent modulation of individual neurons and circuits involves not only structural and functional changes in local synaptic connections, but also a cell-wide arrangement for sustained adaptive responses. Sensory experience-dependent gene expression is an integral mechanism of cell-wide adaptation as it is responsible for the stimulus-specific production and deployment of proteins with various functions in individual neurons, which are required for appropriate adaptive responses. In keeping with this notion, mutations in several genes implicated in the signaling pathways from the synapse to the nucleus have been linked to various neurological diseases such as autism and epilepsy, suggesting that the disruption of activity-dependent gene expression programs under specific circumstances, such as activity-dependent learning can elicit a pathophysiological condition. As such, the study to understand how genetic and epigenetic programs accurately translate sensory information into changes in relevant neural circuits and cognitive behavior bears clinical significance. A recent genome-wide study revealed that a novel class of long non-protein coding RNAs (lncRNAs) called eRNAs (enhancer RNAs) is rapidly expressed from thousands of neuronal enhancers when neurons are excited. The eRNA is quite unique among various types of lncRNAs in that its expression is rapid, transient, and dynamically controlled by sensory stimulation-evoked neuronal activity. The pervasive nature and strong expression correlation with nearby mRNAs suggest a provoking idea that the eRNA might be functionally implicated in the sensory stimulation-induced neural and behavioral plasticity by playing an active role in neural gene expression. Initial analysis of the eRNA function further supports this hypothesis. Given that less than 2% of the mammalian genome accounts for protein-coding genes, an increasing number of mutations associated with neurological diseases will be found to reside in the non-coding regions as human genetic studies continue to advance. The proposed study involves a multidisciplinary approach to examine the role of eRNA in activity-dependent transcription and subsequent changes in synaptic and behavioral plasticity. The eRNA-dependent epigenetic mechanism may represent a new layer of complexity in the molecular architecture of many neurological diseases.

描述（由申请人提供）：