Autism spectrum disorders (ASDs) are associated with disruptions in the development and function of GABAergic neurons¹, which are critical for maintaining the balance of excitation and inhibition in the brain. Genetic studies have implicated histone methyltransferases ASH1L and SETBP1 as high-confidence ASD risk factors. These enzymes regulate chromatin modifications, which in turn influence gene expression, but the mechanisms by which their dysfunction contributes to ASD remain unclear.

Christian Mayer and his team at the Max Planck Institute for Biological Intelligence have conducted preliminary experiments demonstrating that ASH1L and SETBP1 bind to key genomic enhancers, such as the Dlx5/6 enhancer, which regulates the expression of genes critical for GABAergic neuron differentiation. Building on these findings, the proposed research will investigate the protein complexes associated with ASH1L and SETBP1 and their recruitment to enhancers during neuronal development. Genome-wide mapping of their binding sites will reveal how these enzymes regulate chromatin state and lineage-specific gene expression. Functional studies using CRISPR-Cas9-mediated perturbation sequencing in mouse models will examine how disruptions in ASH1L and SETBP1 affect chromatin modifications and the development of GABAergic neurons.

Taken together, this proposal combines advanced genomic, proteomic, and functional approaches to elucidate the roles of ASH1L and SETBP1 in inhibitory neuron development. These studies aim to provide a detailed understanding of how genetic mutations in chromatin-modifying enzymes contribute to altered developmental processes in ASD and related neurodevelopmental disorders.

1. A. Contractor et al. Nat. Neurosci. 24, 1648-1659 (2021) PubMed