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RNF2 Missense Variants Disrupt Polycomb Repression and Enable Ectopic Mesenchymal Lineage Conversion During Human
Stephanie Bielas1,2, Charles Ryan3, Samantha Regan3
1Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, 48109-5618, USA.
None:
Polycomb Repressive Complex 1 (PRC1) catalyzes H2AK119ub1 to facilitate transcriptional repression during development. De novo dominant missense variants in RNF2, the principal E3 ligase of PRC1, are the genetic basis of Luo-Schoch-Yamamoto syndrome. To investigate the developmental impact of catalytically impaired RNF2 alleles, we engineered hESC lines harboring homozygous hypomorphic RNF2 missense alleles (RNF2 MS/MS ) that stably expresses RNF2 but results in reduced H2AK119ub1. Upon directed neural differentiation, RNF2 MS/MS cells exhibited asynchronous neural differentiation and ectopic emergence of mesenchymal fated lineages. Single-cell transcriptomic analyses revealed a fate bifurcation characterized by derepression of TWIST1 and other epithelial-to-mesenchymal transition (EMT) gene-network components, coinciding with focal loss of H2AK119ub1 and H3K27me3. These findings demonstrate that RNF2-mediated H2AK119ub1 is required to constrain lineage fidelity by repressing context-inappropriate developmental programs during early human neural differentiation and reveal a shared chromatin-based mechanism linking RNF2 missense variants to both neurodevelopmental pathology and oncogenic plasticity.
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