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多梳蛋白抑制复合体2（Polycomb repressive complex 2, PRC2）及其催化亚基EZH2（Enhancer of Zeste Homolog 2），可通过介导组蛋白H3第27位赖氨酸的甲基化修饰（H3K27me3），维持基因组调控区域的转录抑制状态，发挥核心生物学功能。PRC2的活性在早期发育过程中至关重要，尤其在皮质发生阶段，其亚基突变可引发多种发育障碍与肿瘤发生。 目前学界关于PRC2功能异常在皮质发生过程中的影响机制仍未完全阐明，相关认知大多基于小鼠模型的研究数据。 为解析EZH2在人类早期皮质发生中的活性机制，本研究针对韦弗综合征（Weaver syndrome, WVS）的分子机制展开探究。韦弗综合征是一种罕见的常染色体显性多系统疾病，由EZH2基因杂合突变所致，临床表现为产前及产后过度生长、巨头畸形、面部形态异常及程度不一的智力障碍。 本研究依托一组极具研究价值的患者特异性模型队列，结合皮质脑类器官发育的纵向时序实验，开展了全面的多组学与功能学分析。 本数据集包含以下内容：i) 批量RNA测序（bulk RNA-seq）的原始计数矩阵与差异表达分析表格；ii) 染色质免疫共沉淀测序（ChIP-seq）与切割与释放测序（Cut&Run）实验的峰位点文件及原始计数数据；iii) 包含脑类器官不同发育阶段单细胞RNA测序（single-cell RNA-seq）数据的h5ad文件；iv) 用于构建基因调控网络（gene-regulatory-networks）及开展数据解读的参考数据集。