INTRODUCTION The brain is responsible for cognition, behavior, and much of what makes us uniquely human. The development of the brain is a highly complex process, and this process is reliant on precise regulation of molecular and cellular events grounded in the spatiotemporal regulation of the transcriptome. Disruption of this regulation can lead to neuropsychiatric disorders. RATIONALE The regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types. Understanding the etiology of neuropsychiatric disorders requires knowledge not just of endpoint differences between healthy and diseased brains but also of the developmental and cellular contexts in which these differences arise. Moreover, an emerging body of research indicates that many aspects of the development and physiology of the human brain are not well recapitulated in model organisms, and therefore it is necessary that neuropsychiatric disorders be understood in the broader context of the developing and adult human brain. RESULTS Here we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood. We observed a widespread transcriptomic transition beginning during late fetal development and consisting of sharply decreased regional differences. This reduction coincided with increases in the transcriptional signatures of mature neurons and the expression of genes associated with dendrite development, synapse development, and neuronal activity, all of which were temporally synchronous across neocortical areas, as well as myelination and oligodendrocytes, which were asynchronous. Moreover, genes including MEF2C, SATB2, and TCF4, with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity. CONCLUSION We generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease. Spatiotemporal dynamics of human brain development and neuropsychiatric risks. Human brain development begins during embryonic development and continues through adulthood (top). Integrating data modalities (bottom left) revealed age- and cell type–specific properties and global patterns of transcriptional dynamics, including a late fetal transition (bottom middle). We related the variation in gene expression (brown, high; purple, low) to regulatory elements in the fetal and adult brains, cell type–specific signatures, and genetic loci associated with neuropsychiatric disorders (bottom right; gray circles indicate enrichment for corresponding features among module genes). Relationships depicted in this panel do not correspond to specific observations. CBC, cerebellar cortex; STR, striatum; HIP, hippocampus; MD, mediodorsal nucleus of thalamus; AMY, amygdala. To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type–specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.

中文翻译：

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人脑发育和神经精神风险的综合功能基因组分析


简介 大脑负责认知、行为以及使我们成为人类的独特因素。大脑的发育是一个高度复杂的过程，这个过程依赖于基于转录组时空调节的分子和细胞事件的精确调节。这种调节的破坏可能导致神经精神疾病。基本原理 人脑的调控、表观基因组和转录组特征尚未跨时间、区域或细胞类型进行全面整理。了解神经精神疾病的病因不仅需要了解健康大脑和患病大脑之间的终点差异，还需要了解这些差异出现的发育和细胞背景。此外，新兴的研究表明，人类大脑发育和生理学的许多方面并没有在模型生物中得到很好的重现，因此有必要在更广泛的发育中和成人大脑的背景下理解神经精神疾病。结果在这里，我们描述了组织和单细胞水平上各种基因组数据模式的生成和分析，包括从胚胎发育到成年的多个大脑区域的转录组、DNA 甲基化和组蛋白修饰。我们观察到广泛的转录组转变始于胎儿发育晚期，并且区域差异急剧减少。 这种减少与成熟神经元的转录特征以及与树突发育、突触发育和神经元活动相关的基因表达的增加相一致，所有这些在新皮质区域以及髓鞘形成和少突胶质细胞中都是异步的。此外，包括 MEF2C、SATB2 和 TCF4 在内的基因，与多种大脑相关特征和疾病具有遗传关联，聚集在少数表现出空间或时空特异性的模块中。结论我们生成并应用我们的数据集来记录人类发育过程中的转录组和表观遗传变化，然后将这些变化与主要的神经精神疾病联系起来。这些数据使我们能够识别基因、细胞类型、基因共表达模块和疾病风险可能集中的时空位点，证明了数据集的实用性，并为人类发展和疾病提供了新的见解。人脑发育和神经精神风险的时空动态。人类大脑的发育从胚胎发育开始，一直持续到成年（上）。整合数据模式（左下）揭示了年龄和细胞类型特定的特性以及转录动态的整体模式，包括晚期胎儿转变（中下）。我们将基因表达的变化（棕色，高；紫色，低）与胎儿和成人大脑中的调节元件、细胞类型特异性特征以及与神经精神疾病相关的遗传位点（右下；灰色圆圈表示相应特征的富集）联系起来模块基因之间）。此面板中描述的关系与具体观察结果并不对应。 CBC，小脑皮质； STR，纹状体； HIP，海马体； MD，丘脑内侧核；艾米，杏仁核。为了扩大我们对人类神经发育的理解，我们分析了整个产前和产后发育过程中大脑区域和/或细胞类型的转录组和表观基因组景观。综合分析揭示了时间、区域、性别和细胞类型特异性的动态。我们观察到一种全局转录组杯形模式，其特征是胎儿过渡晚期，与区域差异急剧减少以及细胞组成和成熟的变化相关，随后在儿童期至青春期发生逆转，并伴有表观基因组重组。基因共表达模块的分析揭示了与表观基因组调控和神经发育过程的关系。与大脑特征和神经精神疾病具有遗传关联的基因（包括 MEF2C、SATB2、SOX5、TCF4 和 TSHZ3）聚集在少数模块和不同的细胞类型中，揭示了对神经发育和神经精神风险的基因组基础的见解。