PRC2 gatekeeps the balance between direct and indirect neurogenesis in human corticogenesis

The polycomb repressive complex 2 (PRC2) and its catalytic subunit EZH2 are essential for maintaining transcriptional repression at genomic regulatory regions through the methylation of lysine 27 on histone 3 (H3K27me3). PRC2 activity is fundamental during early development, particularly in corticogenesis, with mutations in its subunits leading to various developmental disorders and cancers. Our knowledge about the impact of PRC2 dysfunction in corticogenesis is still incomplete and largely based on mouse data. To understand the activity of EZH2 in human early corticogenesis we dissected the molecular mechanisms underlying Weaver syndrome (WVS), a rare autosomal dominant multisystem disorder caused by heterozygous mutations in the EZH2 gene characterized by pre- and post-natal overgrowth, macrocephaly, facial dysmorphisms, and variable intellectual disability. We performed a comprehensive multimodal omic and functional analysis using longitudinal courses of cortical brain organoidogenesis derived from a uniquely informative cohort of patient-specific models. This dataset contains: i) raw counts and differential expression analysis table from bulk RNA-seq; ii) peaks and raw counts for ChIP-seq and Cut&Run data; iii) h5ad file containing single-cell RNA-seq at different stages of organoidogenesis; iv) reference data used to build gene-regulatory-networks and data interpretation