Science. 2018 Dec 14;362(6420). doi: 10.1126/science.aat6720.
Genes implicated in neuropsychiatric disorders are active in human fetal brain, yet difficult to study in a longitudinal fashion. We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were assembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset.
神经精神疾病相关基因在人类胎儿大脑中活跃，但难以进行纵向研究。我们证明，人类多能细胞来源的类器官可在受孕后 16 周之前在分子水平上模拟大脑皮质发育。多组学分析揭示了差异活跃的基因和增强子，最大的变化发生在从干细胞向祖细胞的过渡时期。趋同的基因和增强子模块网络被组装成六个和四个跨越时间的表达和活性的全局模式。一个呈渐进下调趋势的模式富含人类获得的增强子，表明它们在早期人类大脑发育中的重要性。一些趋同的基因和增强子模块在自闭症儿童中富含自闭症相关基因和基因组变异。该类器官模型有助于鉴定可能导致疾病发生的功能元件。
