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.
