Unbalanced chromatin binding of Polycomb complexes drives neurodevelopmental disorders [snMultiome]

Heterozygous de novo missense mutations in genes encoding Polycomb-group (PcG) proteins can cause diverse neurodevelopmental disorders (NDDs), but the underlying mechanisms are not yet understood. Here, we identified novel mutations in the two E3-ligases of the Polycomb Repressive complex 1 (PRC1), RING1 and RNF2, in individuals with NDDs and uncover distinct mechanisms by which PRC1 activity can be compromised. Building on this, and as a proof of concept, we generated embryonic stem cells (ESCs) and a novel mouse model carrying a heterozygous Rnf2 allele with a mutation that produces a deleterious Ring1bR70H variant. This variant causes a cell fate change in neuroprecursors (NPCs) towards the non-neuronal lineages glial and microglia. Allele-specific profiling revealed that Ring1bR70H integrates into canonical PRC1, disrupting the balance of PRC1 complexes by displacing variant PRC1 from chromatin, resulting in PcG target genes upregulation. In mutant NPCs, we uncover an aberrant retention of PcG and chromatin compaction at key NPC pioneer factors and Wnt signaling genes. Critically, a heterozygous Rnf2 mutation in mice is sufficient to disrupt neural connectivity and structural organization in key brain regions, including the medial prefrontal cortex and hippocampus. Our findings establish Rnf2 as essential for neurodevelopmental integrity and brain function, shedding light on how PRC1 dysfunction contributes to NDDs.