Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes

Deleterious variants in POGZ, which encodes a chromatin regulator, are strongly associated with autism spectrum disorder (ASD). However, the neurodevelopmental function of POGZ remained unclear. Here, we show that in the developing mouse forebrain POGZ binds to euchromatic gene regulatory elements, and that Pogz knockout mice exhibit altered chromatin accessibility and gene expression, especially for clusters of synaptic genes. POGZ loss leads to a reduction of active chromatin marks and downregulation of many synapse-related genes. We further demonstrate that POGZ forms a nuclear complex and co-occupies genomic loci with ADNP (another high-confidence ASD gene), and that POGZ regulates the expression of other neurodevelopmental disorder risk genes. Conclusion: POGZ is a key regulator of chromatin state at synaptic gene clusters, linking it to the control of genes important for neurodevelopment and ASD. These results provide a mechanistic insight into how a POGZ mutation might contribute to ASD pathogenesis by dysregulating neuronal gene expression and chromatin structure.