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

PROJECT SUMMARY (See instructions): Autism comprises a class of developmental disorders characterized by significant social, communication, and behavioral challenges. Autism is thought to result from neural cell type imbalance during early development, partly from the discovery of chromatin regulators as genes linked with autism. Yet, the cellular, molecular, behavioral, and developmental mechanisms of these autism-linked 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 autism-linked genes is therefore fundamental to understanding how mutations in these genes leads to cell type imbalances and altered behaviors, affecting physiological well-being. We have 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 autism-linked genes. By screening for behavioral phenotypes in zebrafish morphants, we have prioritized 7 zebrafish lysine methyltransferase genes (corresponding to 5 human genes) for further study: kmt2a, kmt2ca/b, kmt2e, setd1 a, and setd1 b. Despite their overlapping functions as H3K4 lysine methyltransferases, mutations in these genes led to different behavioral phenotypes in morphants. The full developmental and behavioral phenotypes, the cell types and circuits/pathways, and gene regulatory functions that are affected in these mutants, remain unknown. The proposed study will combine behavioral and developmental assays, pharmacological profiling, brain activity assays, and single-cell transcriptomic and chromatin accessibility profiling to directly test the hypothesis that these genes function to specify cell types required for cell type and circuit development and, ultimately, behavioral responses during development. Altogether, findings from this study will uncover unique functional roles and mechanisms for conserved candidate histone modifier autism-linked genes during early development.