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Loss-of-Function Analyses of SETD1A in Human Neural Models

人类神经模型中 SETD1A 的功能丧失分析

基本信息

批准号：
10616753
负责人：
Guo-li Ming
金额：
$ 62.33万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616753
关键词：
3-Dimensional Affect Axon Brain CRISPR/Cas technology Cell Line Cells Complex Data Defect Development Electrophysiology (science)Engineering Enhancers Epigenetic Process Exhibits Exons Family Functional disorder Genes Genetic Genetic Transcription Genetic study Goals Heterozygote Histone H3 Human Human Genetics Image Induced pluripotent stem cell derived neurons Knock-out Loss of Heterozygosity Lysine Memory impairment Mental disorders Methylation Modeling Molecular Morphology Neurodevelopmental Disorder Neuronal Differentiation Neurons Organoids Pathway interactions Patients Phenotype Physiology Population Prevalence Property Resolution Role SET Domain Schizophrenia Short-Term Memory Societies Stress Structure Supporting Cell Synapses System Techniques Variant cell type chromatin immunoprecipitation differential expression epigenomics excitatory neuron experimental study functional genomics genome wide association study genome-wide histone methylation histone methyltransferase induced pluripotent stem cell inhibitory neuron loss of function loss of function mutation molecular phenotype mouse model mutant neural neural model neurodevelopment neurogenesis neuropsychiatric disorder neurotransmission novel therapeutics overexpression pharmacologic premature promoter public health relevance risk variant single nucleus RNA-sequencing socioeconomics stem cell model synaptic function therapeutically effective trait transcriptome transcriptome sequencing transcriptomics

项目摘要

Modified Project Summary/Abstract Section Rare loss-of-function (LoF) mutations in SETD1A are strongly associated with schizophrenia (SZ), a debilitating mental disorder affecting 1% of the population, and other severe neurodevelopmental disorders. SETD1A encodes a component of the histone methyltransferase complex producing mono-, di, and trimethylated histone H3 at Lysine 4 (H3K4). H3K4 trimethylation (H3K4me3) and H3K4me1 are epigenomic marks of active gene transcriptional promoters and enhancers, respectively. Interestingly, histone methylation has also been suggested as one of the most enriched gene pathways in common variant-based genome-wide associations studies (GWAS) of major psychiatric disorders. Furthermore, a recent mouse model with heterozygous knockout of SETD1A exhibited working memory deficits and showed transcriptional changes that overlap with those implicated in neurodevelopmental disorders, however, seemingly independent from a H3K4me3 mechanism. Therefore, it remains largely unclear whether and how SETD1A causes SZ-relevant molecular and cellular changes in a human brain. Our central hypothesis is that human induced pluripotent stem cell (hiPSC)-derived neuronal cells and cortical organoids recapitulate key SZ-relevant epigenetic, molecular and cellular properties of SETD1A LoF in the human brain. Using CRISPR/Cas9 gene editing, we have generated isogenic hiPSC lines carrying heterozygous LoF mutations (in exon 4 and exon 16, on different genetic backgrounds) of SETD1A. Preliminary results showed that mutant lines were defective in cortical organoid development with premature neuronal differentiation at early developmental stages. Furthermore, morphological, electrophysiological and transcriptomic analyses of hiPSC neurons carrying SETD1A LoF mutation showed defective synaptic neurotransmission. Interestingly, genes showing differential expression in both 3D cortical organoids and 2D cultures from mutant lines are enriched for common GWAS risk variants of SZ and other neuropsychiatric disorders/traits, suggesting possible convergent pathways shared by SETD1A LoF and common GWAS risk variants of major psychiatric disorders. Leveraging our respective expertise in hiPSC models and neurogenesis, synaptic physiology and functional genomics within our team, we propose to characterize the molecular and cellular mechanisms underlying the deficits associated with SZ-associated LoF mutations in SETD1A in human neural systems. We will identify the cell-type-specific and developmental stage-specific cellular and molecular phenotypes associated with SETD1A LoF in cortical organoids, and then investigate the synaptic phenotype(s) of SETD1A LoF mutations in human neurons and associated transcriptome changes. The proposed study will enable us to perform a well-controlled assessment of the impact of SETD1A LoF mutations on the molecular and cellular mechanisms underlying deficits in early neurodevelopment and synaptic properties.

修改的项目摘要/摘要部分