Functional mapping of noncoding regulatory variants in human neuronal subtypes

人类神经元亚型非编码调控变异的功能图谱

基本信息

批准号：
10593976
负责人：
Nan Yang
金额：
$ 68.27万
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：
2022
资助国家：
美国
起止时间：
2022-03-18 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593976
关键词：
Affect Alleles Autopsy Binding Biochemical Biological Biological Assay Biological Models Biological Process Biology Brain Brain Diseases Cell model Cells Chromosome Mapping Complex Coupled DNA Sequence Data Derivation procedure Development Diagnosis Disease Elements Enhancers Epigenetic Process Etiology Foundations Functional disorder Future Gene Expression Genes Genetic Genetic Drift Genetic Engineering Genetic Transcription Genome Genome Mappings Genomics Glutamates Goals Heritability Human Human Genetics Human Genome Investigation Knowledge Link Maps Measures Mental disorders Methodology Mission Molecular Neurobiology Neurons Pluripotent Stem Cells Population Process Regulatory Element Reporter Research Research Personnel Resolution Resources Rest Risk Role Sampling Schizophrenia Signal Transduction Societies Specificity Stimulus System Technology Testing Tissues Translating United States National Institutes of Health Untranslated RNA Validation Variant Work artificial neural network autism spectrum disorder brain tissue cell type chromatin modification chromosome conformation capture cohort disability disorder risk epigenomics excitatory neuron family burden genetic variant genome wide association study genome-wide analysis human disease human model human pluripotent stem cell improved induced pluripotent stem cell inhibitory neuron innovation insight interdisciplinary approach nervous system disorder neuropsychiatric disorder next generation sequencing novel novel therapeutic intervention novel therapeutics prevent programs promoter risk variant socioeconomics stem stem cell technology transcription factor

项目摘要

Complex neuropsychiatric disorders, including schizophrenia and autism spectrum disorder (ASD) among others, impose an enormous socioeconomic burden on families and on society. The pathobiological mechanisms are largely unknown, and treatment options are limited and often incompletely effective. During the past decade, advances in human genetics and next-generation sequencing, coupled with expanding cohort sizes, have permitted the identification of thousands of genetic variants that influence risk for neuropsychiatric diseases. Each disease-associated variants identified by genome-wide association studies (GWAS) could provide insights into a biological mechanism that underlies the risk of disease in humans. However, the availability of data is not synonymous with the presence of meaning. The challenge researchers are facing now is the derivation of biological meaning post-GWAS. Particularly, more than 90% of the risk variants are found in the non-coding regions of the human genome. Although the potential contribution of non-coding variants to complex human diseases has long been speculated, it has been a major challenge to develop testable hypotheses to decipher their role in disease etiology. Here, we propose to develop innovative multidisciplinary approaches to bridge the gap between human genetics and experimental biology. The major hypothesis underlying the approach is that epigenetic changes caused by non-coding variation in the cis-regulatory elements, particularly enhancers that are platforms for sequence-specific transcription factor binding and can influence gene transcription over long distance, may confer disease liability by disrupting gene expression. We aim to (i) annotate functionally distinct enhancers in disease-relevant human neuronal subtypes generated by reprogramming of pluripotent stem cells, (ii) apply the cutting-edge HiChIP technology to profile the promoter-enhancer interactions in neurons in resting and active states, and identify the target genes of enhancers, finally, (iii) we will determine how disease- associated variants affect enhancer activity in human neurons. Such effort will provide the foundation to map and prioritize non-coding risk variants for future mechanistic studies. Especially, the enhancer-interactome analysis performed in this study will provide a physical-interaction-based approach for the identification of enhancer target genes in neurons. The information will lay the groundwork for developing testable hypotheses to elucidate the molecular impact of risk variants in non-coding regions. Last but not least, determining how non- coding risk variants disrupt activity-regulated gene expression in neuronal subtypes may uncover novel disease- relevant biology not observed using the incomplete existing methodologies and resources (activity-responsive enhancers are not possible to identify from post-mortem tissue). Once accomplished, the proposed work will have broad impact on translating genetic discoveries into actionable biological hypotheses that can potentially power a new round of development of novel therapeutics strategies for complex neuropsychiatric disorders.

复杂的神经精神疾病，包括精神分裂症和自闭症谱系障碍（ASD）等，给家庭和社会带来巨大的社会经济负担。其病理生物学机制是很大程度上未知，治疗选择有限且往往不完全有效。在过去的十年里，人类遗传学和下一代测序的进步，加上队列规模的扩大，已经允许识别数千种影响神经精神疾病风险的遗传变异。全基因组关联研究 (GWAS) 发现的每种疾病相关变异都可以提供见解探究人类疾病风险背后的生物机制。然而，数据的可用性并不与意义的存在同义。研究人员现在面临的挑战是推导 GWAS 后的生物学意义。特别是，90%以上的风险变异都存在于非编码环境中。人类基因组的区域。尽管非编码变异对复杂人类的潜在贡献疾病长期以来一直被推测，发展可检验的假设来破译一直是一个重大挑战它们在疾病病因学中的作用。在这里，我们建议开发创新的多学科方法来弥合人类遗传学和实验生物学之间的差距。该方法的主要假设是由顺式调控元件的非编码变异引起的表观遗传变化，特别是增强子是序列特异性转录因子结合的平台，可以长期影响基因转录距离，可能会通过破坏基因表达而导致疾病发生。我们的目标是 (i) 注释功能上不同的通过多能干细胞重编程产生的疾病相关人类神经元亚型的增强子， (ii) 应用尖端的 HiChIP 技术来分析静息神经元中启动子-增强子的相互作用和活性状态，并确定增强子的目标基因，最后，（iii）我们将确定疾病如何- 相关变异影响人类神经元的增强子活性。这些努力将为绘制地图奠定基础并优先考虑非编码风险变异以供未来的机制研究。特别是增强子相互作用组本研究中进行的分析将提供一种基于物理交互的方法来识别神经元中的增强子靶基因。这些信息将为开发可检验的假设奠定基础阐明非编码区风险变异的分子影响。最后但并非最不重要的一点是，确定如何非编码风险变异破坏神经元亚型中活动调节的基因表达可能会发现新的疾病使用不完整的现有方法和资源（活动响应不可能从死后组织中识别出增强子）。一旦完成，拟议的工作将对于将遗传发现转化为可操作的生物学假设具有广泛的影响，这些假设有可能推动新一轮复杂神经精神疾病新型治疗策略的开发。