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Novel regulation and function of the lncRNA Gomafu in human neurons

人类神经元中 lncRNA Gomafu 的新调控和功能

基本信息

批准号：
10176618
负责人：
Yue Feng
金额：
$ 55.6万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176618
关键词：
3-Dimensional Affect Alternative Splicing Autopsy Binding Biological Markers Biology Brain Brain Diseases CRISPR/Cas technology Cell Maintenance Code Cognition Disorders Cognitive Complex Data Development Diagnosis Disease Epigenetic Process Epilepsy Etiology Evolution Gene Expression Genes Genetic Genetic Transcription Human Impairment Induced pluripotent stem cell derived neurons Intellectual functioning disability Interneurons Knockout Mice Knowledge Lead Mediating Mental disorders MicroRNAs Midbrain structure Molecular Mus Mutation Myocardial Infarction Names Neurodegenerative Disorders Neuronal Differentiation Neurons Nuclear Nucleotides Open Reading Frames Organoids Pathogenesis Pathway interactions Patients Play Polypyrimidine Tract-Binding Protein Prosencephalon Proteins RNA Regulation Reporting Rodent Role Schizophrenia Synapses Synaptic plasticity Testing Therapeutic Tissues Transcript Transcription Repressor Untranslated RNA anxiety-like behavior autism spectrum disorder cell type conditioned fear dopaminergic neuron epigenetic regulation excitatory neuron gray matter histone modification induced pluripotent stem cell infancy knock-down nerve stem cell nervous system disorder neural network neurogenesis neuron development neuropsychiatric disorder neuropsychiatry novel promoter psychostimulant risk variant schizophrenia risk synaptic function synaptogenesis transcription factor transcriptome transcriptome sequencing

项目摘要

Recent studies identified a fast growing list of long noncoding RNAs (lncRNAs) that harbor greater than 200 nucleotides with no open reading frames but play key roles in regulating gene expression thus govern neural stem cell maintenance, neurogenesis, neuronal network assembly, and synaptic plasticity. The lncRNA transcriptome is strikingly expanded in human during evolution and most abundantly expressed in the brain. The complexity of human lncRNAs is thought to underlie the major architect of cognitive evolution but also introduce vulnerabilities for various brain diseases. Indeed, lncRNA dysregulation is observed in autism, intellectual disability, epilepsy, neurodegenerative disorders and neuropsychiatric diseases, suggesting that lncRNA dysregulation contributes to the pathogenesis of various brain illnesses. However, our current understanding of regulation and function of lncRNAs in human neurons are still in the infancy. The lncRNA Gomafu, a transcript initially identified to associate with myocardial infarction thus named MIAT, was recently found to be most abundant in the brain and implicated in normal neuronal development and cognitive conditions. Gomafu is quickly downregulated upon synaptic stimulation and fear-conditioning. In addition, Gomafu knockout mice display anxiety-like behaviors. In neurons derived from human induced- pluripotent stem cells (hiPSCs), Gomafu regulates alternative splicing (AS) of primary transcripts essential for neuronal development and synaptic function. Importantly, Gomafu dysregulation is detected in cortical grey matters and interneurons of post-mortem brains derived from schizophrenia patients. These discoveries together suggest that Gomafu plays essential roles in governing normal brain function. However, molecular mechanisms that regulate human Gomafu expression remain unexplored. How Gomafu is dysregulated in brain diseases is not understood. Moreover, how Gomafu controls AS of the human neuronal transcriptome remains elusive. How Gomafu deficiency affects human neuron development is unknown. This proposal attacks these important questions, aiming to 1) Delineate molecular mechanisms and pathways that regulate Gomafu expression in hiPSC-derived neurons, especially regarding a genetic-epigenetic interaction network centering on a novel microRNA-lncRNA functional interplay revealed by our preliminary data; 2) determine the alternative splicing targets of Gomafu in human neuronal transcriptome by deep RNA-sequencing; 3) determine the function of Gomafu in the development of hiPSC-derived cortical excitatory neurons and dopaminergic neurons in 2-D culture and 3-D organoids. Answers to these questions will fill prevailing knowledge gaps regarding how lncRNAs govern normal development of human neurons and lncRNA malfunction in brain disorders.

最近的研究发现了一个快速增长的长链非编码rna （lncrna）列表，其中包含大于