A hidden player in genome architecture: PRR12 in cohesin dynamics and NOC1 syndrome

Neurodevelopmental disorders frequently arise from mutations in genes controlling chromatin architecture and cohesin-mediated genome organization, underscoring the critical role of 3D genome regulation in brain development. PRR12 is an evolutionarily conserved protein whose molecular function remains poorly defined, despite emerging genetic links to neurodevelopmental phenotypes. In this study, the role of PRR12 in cohesin regulation and chromatin organization was investigated. Loss of PRR12 in neuroblastoma cells led to widespread transcriptional alterations, significantly enriched for cell cycle and chromatin-associated pathways, suggesting a functional involvement in genome regulatory mechanisms. To elucidate the molecular basis underlying these effects, structural predictions generated using AlphaFold identified conserved interaction interfaces between PRR12 and cohesin-associated factors, including STAG1/2-RAD21 and MAU2. Guided by these structural models, targeted mutations were introduced into conserved residues predicted to mediate these interactions. Notably, disruption of the predicted STAG1/2-RAD21-binding interface was associated with detectable chromatin and genome organization phenotypes. These findings suggest that the interaction between PRR12 and STAG2/RAD21 may be particularly relevant for genome regulation. Consistently, genome-wide chromatin conformation analyses revealed alterations in chromatin compartmentalization and loop organization in PRR12 mutant cells, indicating an impact on higher- order chromatin architecture. Finally, FRAP experiments revealed that PRR12 selectively modulates the chromatin dynamics of STAG2-containing cohesin complexes during G1 phase, while no comparable effect was observed on STAG1-cohesin. These results are consistent with a model in which PRR12 contributes to genome organization by differentially influencing the chromatin association and stability of distinct cohesin complexes. Collectively, these findings identify PRR12 as a previously uncharacterized modulator of cohesin stability and genome architecture, providing mechanistic insight into how its dysfunction may contribute to neurodevelopmental disease.