PRC1 Mediates the Transcriptional Repressive Function of POGZ in Neurodevelopmental Gene Regulation

Polycomb Repressive Complex 1 (PRC1) is a family of fundamental epigenetic regulators crucial for gene silencing and mammalian development. Elucidating the PRC1 composition and function in context- and stage-specific functions during differentiation and development is crucial in understanding the impact of PRC1-mediated transcriptional activity in these processes. This study focuses on the identification and characterization of POGZ, a high-risk Autism risk gene, as a novel component of the PRC1 complex in neural cells. Our biochemical analyses demonstrate that POGZ specifically interacts with the PRC1.6 complex to form the novel PRC1-POGZ complex. Functional assays indicate that POGZ elicits strong transcriptional repressor activity that is dependent on RING1B expression. ChIP-Seq studies determined that PRC1-POGZ localizes at neurodevelopmental genes in the embryonic mouse cortex. Although POGZ knockout (KO) does not compromise mESC pluripotency, POGZ ablation in neural precursor cells resulted in severe dysregulation of transcriptomic gene expression, marked by failed activation of key neural marker genes. Mechanistically, PRC1-POGZ target genes involved in multiple aspects of neuronal differentiation were differentially expressed in POGZ KO NPCs, which may explain the observed failed differentiation. The insights gained herein provide critical insights toward understanding how PRC1-POGZ function influences neural cell fate determination.