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

Oliveira, M. M.; Liu, Y.; Erdin, S.; Gao, D.; Bhavsar, R.; Mohajeri, K.; O'Keefe, K.; Boone, P. M.; Xavier, G.; Liao, C.; Li, A.; Yadav, R.; Salani, M.; Lucente, D.; Currall, B.; de Esch, C. E. F.; Tai, D. J. C.; Ruderfer, D.; Brennand, K. J.; Gusella, J. F.; Talkowski, M. E.

doi:10.1101/2025.10.27.684870

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bioRxiv · 10.1101/2025.10.27.684870

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

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Abstract

One of the seminal discoveries from genetic studies of autism spectrum disorder and related neurodevelopmental disorders (NDD) has been that loss-of-function (LoF) mutations in many genes that impact chromatin and transcriptional regulation confer substantial liability to NDD. Haploinsufficiency of the epigenetic regulator POGZ represents one of the strongest such associations; however, little is known about the direct or indirect regulatory targets of POGZ, or the mechanisms by which loss of this chromatin modifier alters early neuronal development and synaptic functions. Here, we created an allelic series of CRISPR-engineered human induced pluripotent stem cell (hiPSC) clones harboring mono- and biallelic POGZ deletions. In hiPSC-derived neural stem cells (NSC) and Neurogenin 2-induced neurons (iN), POGZ LoF altered the expression of genes associated with critical cellular processes and neuronal functions, including synaptic and intracellular signaling and extracellular matrix organization. Our multiomics profiling also showed altered footprinting of critical transcription factors (e.g., activator protein 1 complexes) that were enriched at promoters of differentially expressed genes associated with synaptic function. To further interrogate the shared molecular changes in neuronal development associated with NDD and POGZ regulation, we compared our results to deletions of the transcription factor MEF2C and the sodium channel gene SCN2A that we generated in these same isogenic iN. These analyses revealed strong enrichment of extracellular matrix and intracellular signaling disruption associated with POGZ and MEF2C deletion, whereas POGZ and SCN2A haploinsufficiency exhibited shared transcriptional effects on gene modules enriched for NDD-associated genes with opposing regulatory effects. Notably, we also observed alterations to synaptic firing rate and neurite extension with biallelic deletions, but not heterozygous lines, suggesting subtle effects in neuronal development associated with haploinsufficiency. Overall, these shared molecular consequences suggest key points of convergence that connect epigenetic regulation to neuronal function in the etiology of neurodevelopmental pathologies.

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Oliveira, M. M., Liu, Y., Erdin, S., Gao, D., Bhavsar, R., Mohajeri, K., O'Keefe, K., Boone, P. M., Xavier, G., Liao, C., Li, A., Yadav, R., Salani, M., Lucente, D., Currall, B., de Esch, C. E. F., Tai, D. J. C., Ruderfer, D., Brennand, K. J., Gusella, J. F., Talkowski, M. E.. 2025-10-27. CRISPR-engineered deletion of POGZ alters transcription factor binding at promoters of genes involved in synaptic signaling. https://doi.org/10.1101/2025.10.27.684870

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