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

项目总结

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.