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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：
10371323
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/10371323
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 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 Mathematics Methyltransferase Modeling Molecular Molecular Conformation Mutation Nervous system structure Neurodevelopmental Disorder Neurons Pathway interactions Pattern Pharmacology Phenotype Play Population Resolution Role Severities Shapes Signal Pathway Stimulus Structure Symptoms System Testing To specify 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 neurodevelopment next generation sequencing novel programs relating to nervous system risk variant screening single-cell RNA sequencing social communication 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