Unbalanced chromatin binding of Polycomb complexes drives neurodevelopmental disorders

Area of Science:

• Epigenetics
• Neuroscience
• Developmental Biology

Background:

• Neurodevelopmental disorders (NDDs) are increasing in children, but their causes are often unknown.
• Polycomb repressive complex 1 (PRC1) plays a crucial role in gene regulation during development.

Purpose of the Study:

• To investigate the role of RING1 and RNF2 mutations in NDDs.
• To elucidate the molecular mechanisms by which these mutations affect PRC1 activity and neurodevelopment.

Main Methods:

• Identification of heterozygous mutations in RING1 and RNF2 in individuals with NDDs.
• Development of cellular and mouse models with the Ring1b^R70H variant.
• Allele-specific profiling to analyze PRC1 assembly and chromatin binding.
• Assessment of neurogenesis, brain structure, and behavior in Rnf2 mutant mice.

Main Results:

• Ring1b^R70H variant disrupts PRC1/PRC2 recruitment balance and mis-regulates Polycomb target genes.
• Aberrant Wnt signaling suppression in Rnf2^WT/R70H neuroprecursors leads to halted neurogenesis.
• Rnf2^R70H/R70H mice are perinatally lethal; heterozygotes show altered brain structure and behavioral deficits (reduced sociability, increased anxiety).

Conclusions:

• Mutations in RNF2 disrupt PRC1 chromatin occupancy, contributing to NDDs.
• Epigenetic dysregulation by RNF2 mutations is a key mechanism underlying neurodevelopmental deficits.
• Findings highlight the essential role of PRC1 regulation in neurodevelopmental integrity and brain function.