CRISPR-engineered deletion of POGZ alters transcription factor binding at promoters of genes involved in synaptic signaling

One of the seminal discoveries from genetic studies of autism and related neurodevelopmental disorders is that loss-of-function mutations in many chromatin regulators confer substantial NDD risk. Haploinsufficiency of POGZ is one of the strongest such associations; however, the mechanisms by which POGZ loss disrupts neural development are not fully known. In this preprint, the authors created an allelic series of POGZ knockouts in human induced pluripotent stem cells (iPSCs) using CRISPR/Cas9. They differentiated these isogenic lines into neural stem cells (NSCs) and neurons. Results: POGZ loss-of-function altered expression of genes involved in synaptic signaling and extracellular matrix organization. Multi-omics profiling (ATAC-seq and RNA-seq) revealed that POGZ deficiency led to changes in transcription factor binding (e.g., AP-1 complex) at promoters of differentially expressed genes. Comparing POGZ knockouts to parallel knockouts of MEF2C and SCN2A in neurons showed both overlapping and distinct molecular effects, with shared dysregulation of pathways related to neurodevelopment. Notably, biallelic POGZ deletions (but not heterozygous) impaired neuronal firing rates and neurite outgrowth, suggesting that haploinsufficiency causes subtler effects. Conclusion: POGZ loss derails transcriptional networks and chromatin states critical for neuronal development, highlighting points of convergence with other NDD genes (like MEF2C and SCN2A). This preprint provides mechanistic insight into how POGZ mutations contribute to neurodevelopmental disorders. (Not yet peer-reviewed.)