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

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.