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Functional analysis of histone modifier Autism Spectrum Disorders risk genes in vertebrate development

组蛋白修饰自闭症谱系障碍风险基因在脊椎动物发育中的功能分析

基本信息

批准号：
10685941
负责人：
Valerie Angela Tornini
金额：
$ 11.93万
依托单位：
YALE UNIVERSITY
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：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10685941
关键词：
ASD patient Affect Behavior Behavioral Behavioral Assay Binding Sites Biological Assay Brain Brain region Cell physiology Cells Characteristics Child Child Health Chromatin Code Communication Computer Analysis DNA Data Defect Development Dissection Ensure Enzymes Epigenetic Process Etiology Fingerprint Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Histone-Lysine N-Methyltransferase Histones Human Human Development Human Genetics Hyperactivity Individual Lysine MLL gene Maps Mathematics Methyltransferase Modeling Molecular Molecular Conformation Mutation Nervous System Neurodevelopmental Disorder Neurons Pathway interactions Pattern Phenotype Play Population Resolution Role Severities Shapes Signal Pathway Specific qualifier value Stimulus Structure Symptoms System Testing United States Variant Vertebrates Zebrafish autism spectrum disorder behavioral phenotyping behavioral response brain cell cell type cohort de novo mutation developmental disease gene regulatory network histone modification in vivo insight loss of function mutant neural neurodevelopment next generation sequencing novel pharmacologic programs risk variant screening single-cell RNA sequencing social tool transcription factor transcriptomics

项目摘要

PROJECT SUMMARY Autism Spectrum Disorders (ASD) are a class of developmental disorders characterized by significant social, communication, and behavioral challenges. ASD is thought to result from neural cell type imbalance during early development, partly from the discovery of histone modifiers and chromatin regulators as ASD risk genes. Unfortunately, the cellular, molecular, behavioral, and developmental mechanisms of these ASD risk genes are not well known. This is underscored by the wide variation in type and severity of symptoms. Systematic dissection of the roles of candidate histone modifier ASD risk genes is therefore fundamental to understanding how mutations in these genes leads to cell type imbalances and altered behaviors. Recently, our lab has taken advantage of the fast-developing vertebrate system zebrafish, in which histone modifier genes are highly conserved, to identify behavioral and developmental phenotypes in mutants of candidate risk genes. Mutants in one of these genes, the lysine methyltransferase kmt2a/mll1, display severe nighttime hyperactivity and altered cell type specification in the brain. The full developmental and behavioral phenotypes, or the cell types and circuits/pathways that are affected in these mutants, remain unknown. The proposed study will combine behavioral and developmental assays, brain activity assays, and single-cell transcriptomic and chromatin accessibility profiling to directly test the hypothesis that kmt2a functions to specify cell types required for appropriate nighttime activity behavioral responses during development. Altogether, findings from this study will uncover unique functional roles and mechanisms for conserved candidate histone modifier ASD risk genes during early development.

项目总结自闭症谱系障碍(ASD)是一类发育障碍，其特征是显著的社会性、沟通和行为挑战。ASD被认为是由于神经细胞类型失衡导致的早期发展，部分原因是发现了组蛋白修饰物和染色质调节剂作为ASD风险基因。不幸的是，这些ASD风险基因的细胞、分子、行为和发育机制是不太为人所知。症状的类型和严重程度差异很大，突显了这一点。系统化因此，剖析候选的组蛋白修饰物ASD风险基因的作用是理解这些基因的突变是如何导致细胞类型失衡和行为改变的。最近，我们实验室利用了快速发展的脊椎动物系统斑马鱼，其中组蛋白修饰基因是高度保守的，用来识别突变体的行为和发育表型候选风险基因。其中一个基因的突变，赖氨酸甲基转移酶kmt2a/MLL1，表现出严重的夜间多动，改变了大脑中的细胞类型。全面发展和行为表型，或在这些突变体中受到影响的细胞类型和电路/通路，仍然未知。这个拟议的研究将结合行为和发育分析、大脑活动分析和单细胞转录和染色质可及性分析，以直接测试kmt2a发挥作用的假设指定发育过程中适当的夜间活动行为反应所需的细胞类型。总之，这项研究的发现将揭示保守性的独特的功能作用和机制候选的组蛋白修饰物ASD风险基因在早期发育中。