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Remodeling of chromatin and transcriptomic landscape to enhance optic nerve regeneration

重塑染色质和转录组景观以增强视神经再生

基本信息

批准号：
10029812
负责人：
Fengquan Zhou
金额：
$ 44.81万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10029812
关键词：
ATAC-seq Affect Axon Bioinformatics Brain CRISPR/Cas technology Candidate Disease Gene Cell Maturation Cell Survival Cells ChIP-seq Chromatin Chromatin Structure Collaborations Cytoskeleton Data Development Environment Epigenetic Process Gene Expression Gene Targeting Genes Genetic Transcription Goals Growth Factor In Vitro Injury Knock-out Lead Molecular Molecular Target Multiomic Data Mus Natural regeneration Neurons Nonmuscle Myosin Type IIA Optic Chiasm Optic Nerve Optic Nerve Injuries Pathway interactions Protocols documentation RNA Recovery of Function Regulation Retinal Ganglion Cells Role Site Spinal cord injury Survival Rate Three-Dimensional Imaging Tissues Vision Visual Visual system structure Work XCL1 gene aged axon regeneration base chromatin remodeling experimental study genomic locus histone demethylase imaging study in vivo injured innovation multiple omics nerve injury non-muscle myosin novel optic nerve regeneration regenerative screening tool transcription factor transcriptome sequencing transcriptomics

项目摘要

Summary Long distance axon regeneration is one of the most important aspects and a prerequisite for successful functional recovery after optic nerve injuries. Although great progress has been made to enhance the intrinsic axon regeneration ability via various approaches, long distance optic nerve regeneration reaching the original targets in the brain remains a major challenge. We think that extending sufficient number of injured RGC axons from different RGC subtypes into the brain should be the major tasks for functional recovery after visual injuries. Therefore, a new strategy is needed to 1) enhance RGC survival rate, 2) identify additional gene targets capable of enhance regeneration from a diverse subtypes of RGCs, and 3) promote extensive long-distance optic nerve regeneration that is less affected by the inhibitory environment. During RGC maturation, their chromatin structures change temporally, leading to changed transcriptomics underlying the loss of intrinsic ability to support axon regeneration. Conversely, the current identified genes that act to enhance optic nerve regeneration presumably alter the developmental changes in transcriptomics in some way. Thus, it is important to reveal the chromatin and transcriptomics landscape of RGCs favorable for axon regeneration, and identify key transcription factors and/or chromatin modulators underlying such chromatin state of regenerating RGCs. In Aim 1, by performing RNA-seq, ATAC-seq and ChIP-seq of purified RGCs at different maturation stages, and different regenerative states, we will use advanced integrative bioinformatics analyses to reveal the chromatin and transcriptomics landscape of RGCs favorable for axon regeneration, and identify key transcription factors and/or chromatin modulators underlying such chromatin state of regenerating RGCs. In Aim 2, we will perform functional screening experiments to determine their roles in regulation of RGC survival and/or optic nerve regeneration, and their underlying mechanisms. Our recent work showed that deleting non-muscle myosin IIA/B or histone demethylase UTX, when combined with enhanced intrinsic axon regeneration ability, could lead to extensive long-distance optic nerve regeneration. Based on these results, in Aim 3, we will explore if combining the newly identified transcription factors with UTX and myosin IIA/B knockout could induce long distance optic nerve regeneration into the brain. The proposed studies will not only generate a detailed picture of changes in transcriptomics, chromatin accessibility and epigenetic landscape of RGCs during maturation and regeneration, but also identify novel molecular targets and optimized approaches to re-establish visual circuity.

总结