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

项目摘要 自闭症谱系障碍（ASD）是一类发育障碍，其特征在于显著的社会， 沟通和行为挑战。ASD被认为是由于神经细胞类型的不平衡， 早期发展，部分来自组蛋白修饰剂和染色质调节剂作为ASD风险基因的发现。 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确定的。 不太出名。这是强调的广泛变化的类型和严重程度的症状。系统 因此，对候选组蛋白修饰剂ASD风险基因的作用的剖析是理解ASD风险基因的基础。 这些基因的突变如何导致细胞类型失衡和行为改变。 最近，我们的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，以确定行为和发育表型的突变体， 候选风险基因。这些基因之一的突变体，赖氨酸甲基转移酶kmt 2a/mll 1，显示严重的 夜间活动过度和大脑中细胞类型的改变。全面的发展和行为 在这些突变体中受影响的表型或细胞类型和回路/途径仍然未知。的 拟议的研究将结合联合收割机的行为和发育分析，大脑活动分析，和单细胞 转录组和染色质可及性分析，以直接检验KMT 2A的功能是 指定发育期间适当夜间活动行为反应所需的细胞类型。 总而言之，这项研究的结果将揭示保守基因的独特功能作用和机制。 候选组蛋白修饰剂ASD风险基因在早期发展。

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.