Michigan State University has received a USD 1.03 million National Institute of Mental Health RF1 award to investigate how loss-of-function mutations in the histone methyltransferase ASH1L contribute to autism spectrum disorder (ASD), with the work running through April 2028.
ASH1L has emerged from large-cohort genetic studies as one of the highest-confidence ASD risk genes, with clinical reports documenting de novo ASH1L mutations in affected children. Prior work from the same group demonstrated that conditional deletion of Ash1l in the mouse brain produced autistic-like behaviors, cognitive deficits, and neural hyperactivity consistent with excitation/inhibition (E/I) imbalance — a circuit-level phenotype increasingly implicated across multiple ASD subtypes. Notably, postnatal administration of vorinostat (SAHA), a histone deacetylase inhibitor, ameliorated behavioral and cognitive deficits in Ash1l-deficient mice, suggesting that ASH1L-mediated histone methylation and histone acetylation act synergistically to regulate brain function.
The funded work will use Ash1l conditional knockout mice to map cell-type-specific contributions to the observed phenotypes, profiling transcriptomes and epigenomes separately across cortical excitatory neurons, inhibitory neurons, and astrocytes. The aim is to identify which neural lineages drive E/I imbalance and which gene networks are disrupted downstream of ASH1L loss — information that could point toward more targeted intervention strategies.
The translational hook is the vorinostat observation. While the preclinical finding requires substantial further validation before any clinical inference is warranted, it positions ASH1L-associated ASD within a broader effort to identify epigenetic targets amenable to pharmacological modulation. Several other high-confidence ASD risk genes, including ADNP and CHD8, also encode chromatin regulators, reinforcing interest in this mechanistic space. No approved therapies currently target ASH1L directly.