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3D Genome Mapping in the Human Brain and its Implications for Schizophrenia

人脑 3D 基因组图谱及其对精神分裂症的影响

基本信息

批准号：
9898467
负责人：
Prashanth Rajarajan
金额：
$ 5.05万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-05 至 2021-04-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898467
关键词：
3-Dimensional Adult Affect Architecture Astrocytes Autopsy Brain Brain Diseases Cell physiology Chromatin Chromatin Loop Clustered Regularly Interspaced Short Palindromic Repeats Data Data Set Development Diagnosis Diagnostic Disease Distal Doctor of Philosophy Enhancers Epigenetic Process Future Gene Expression Genes Genetic Transcription Genome Genome Mappings Genomics Genotype Human Human Genome In Situ In Vitro Individual Investigation Knowledge Libraries Mental disorders Molecular Conformation Neurobiology Neuroglia Neurons Positioning Attribute Process Publishing Quality Control Regulatory Element Risk Role Schizophrenia Structure Techniques Therapeutic Transcription Initiation Site United States Untranslated RNA Validation Variant arm base brain tissue cell type chromosome conformation capture disorder risk excitatory neuron genome wide association study induced pluripotent stem cell innovation insight nerve stem cell neurobiological mechanism promoter relating to nervous system risk variant stem cell model tool transcriptome sequencing

项目摘要

PROJECT SUMMARY The human genome has traditionally been studied as a linear entity, ignoring how three-dimensional looping interactions that bring together distal non-coding regulatory elements and proximal promoters may modulate gene expression. Even with innovations in chromosome conformation capture techniques, the 3D neuroepigenome remains largely underexplored. Exploration of cell-type-specific chromosomal conformations will advance insight into hitherto unknown roles of non-coding sequences in the neurobiology of psychiatric disorders such as schizophrenia. The basic mechanisms of these processes can be elucidated using a human induced pluripotent stem cell-based platform, where isogenic neural cell types can be inexhaustibly derived from one individual. In this proposal, we seek to explore how 3D chromatin interactions and topology change based on cell type given an identical genotypic background in normal human neural differentiation, from neural progenitor to either astrocyte or excitatory neuron. I hypothesize that identity-specific regulatory element- promoter loops will emerge that connect noncoding sequences to transcription start sites, thereby modulating gene expression. By overlaying known schizophrenia “risk loci,” many of which are in noncoding regions, on neuron-specific chromatin loops, I will attempt to find those loci that occur in sequences of the genome critical for loop formation. Finally, I hypothesize that by manipulating such candidate (i.e., risk-loci-bearing) loops with targeted CRISPR epigenetic editing, I will observe changes in gene expression. Findings from the proposed project will greatly advance knowledge in the field of how the 3D genome can quite literally contribute to the risk architecture of psychiatric disease, promoting the development of more effective diagnosis and treatment in the future.

项目总结传统上，人类基因组被作为一个线性实体来研究，而忽略了三维环路是如何将远端非编码调控元件和近端启动子聚集在一起的相互作用可能会调节基因表达。即使在染色体构象捕捉技术方面有所创新，3D 神经表观基因组在很大程度上仍未得到充分研究。细胞类型特异性染色体构象的探索将促进对非编码序列在精神病学神经生物学中迄今未知的作用的洞察精神分裂症等精神障碍。这些过程的基本机制可以用人类基于诱导多能干细胞的平台，在这里可以取之不尽的同源神经细胞类型从一个人身上。在这个方案中，我们试图探索3D染色质相互作用和拓扑变化基于在正常人类神经分化中给予相同基因背景的细胞类型，从神经细胞星形胶质细胞或兴奋性神经元的祖细胞。我假设特定身份的监管元素- 启动子环将出现，将非编码序列连接到转录起始点，从而调节基因表达。通过叠加已知的精神分裂症“风险基因”，其中许多位于非编码区，神经元特有的染色质环，我将尝试找到那些出现在基因组序列中的关键基因座用于形成环路。最后，我假设，通过操纵这样的候选(即，承担风险的)循环针对CRISPR表观遗传编辑，我将观察基因表达的变化。建议的调查结果该项目将极大地促进3D基因组如何真正地对精神疾病的风险架构，促进更有效的诊断和治疗的发展在未来。