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类器官体单细胞测序揭示人类大脑发育特征
作者:小柯机器人 发布时间:2019/10/17 14:17:36

德国马克斯·普朗克进化人类学研究所J. Gray Camp、Barbara Treutlein和Zhisong He等研究人员合作绘制了大脑类器官体的单细胞基因组图谱,从而揭示了人类特异的大脑发育特征。该项研究成果2019年10月16日在线发表于国际学术期刊《自然》。

研究人员使用单细胞转录组学和染色质可及性测序分析了干细胞来源的脑类器官体,以研究特定于人类的基因调节变化。

研究人员首先分析了人类全脑器官形成过程中从多能性到神经外胚层和神经上皮阶段的细胞组成,并重建了分化轨迹,然后在背侧和腹侧前脑、中脑和后脑区域内分化为神经元命运。来自不同iPSC品系类器官的大脑区域组成各不相同,但是区域基因表达模式在各个个体之间仍可大致再现。研究人员分析了黑猩猩和猕猴的大脑类器官体,发现与其他两个灵长类动物相比,人类神经元的发育速度较慢。使用分化路径的拟时态比对,研究人员发现人类特异性基因表达沿皮质的祖细胞到神经元谱系解析为不同的细胞状态。染色质的可及性在皮层发育过程中是动态的,研究人员发现人与黑猩猩之间可及性的差异与人特异性基因表达和遗传变化有关。

最后,研究人员使用单核RNA测序分析绘制了成年人前额叶皮层中人特异性的表达图,并确定了成年后持续存在的发育差异以及仅在成年大脑中发生的细胞状态特异性变化。这些数据提供了大猿前脑发育的时序细胞图谱,并阐明了人类独有的动态基因调控功能。

据悉,自从人类脱离黑猩猩和其他大猿以来,人类的大脑发生了巨大变化。但是,导致这种差异的遗传和发育程序尚未完全被理解。

附:英文原文

Title: Organoid single-cell genomic atlas uncovers human-specific features of brain development

Author: Sabina Kanton, Michael James Boyle, Zhisong He, Malgorzata Santel, Anne Weigert, Ftima Sanchs-Calleja, Patricia Guijarro, Leila Sidow, Jonas Simon Fleck, Dingding Han, Zhengzong Qian, Michael Heide, Wieland B. Huttner, Philipp Khaitovich, Svante Pbo, Barbara Treutlein, J. Gray Camp

Issue&Volume: 2019-10-16

Abstract: 

The human brain has undergone substantial change since humans diverged from chimpanzees and the other great apes1,2. However, the genetic and developmental programs that underlie this divergence are not fully understood. Here we have analysed stem cell-derived cerebral organoids using single-cell transcriptomics and accessible chromatin profiling to investigate gene-regulatory changes that are specific to humans. We first analysed cell composition and reconstructed differentiation trajectories over the entire course of human cerebral organoid development from pluripotency, through neuroectoderm and neuroepithelial stages, followed by divergence into neuronal fates within the dorsal and ventral forebrain, midbrain and hindbrain regions. Brain-region composition varied in organoids from different iPSC lines, but regional gene-expression patterns remained largely reproducible across individuals. We analysed chimpanzee and macaque cerebral organoids and found that human neuronal development occurs at a slower pace relative to the other two primates. Using pseudotemporal alignment of differentiation paths, we found that human-specific gene expression resolved to distinct cell states along progenitor-to-neuron lineages in the cortex. Chromatin accessibility was dynamic during cortex development, and we identified divergence in accessibility between human and chimpanzee that correlated with human-specific gene expression and genetic change. Finally, we mapped human-specific expression in adult prefrontal cortex using single-nucleus RNA sequencing analysis and identified developmental differences that persist into adulthood, as well as cell-state-specific changes that occur exclusively in the adult brain. Our data provide a temporal cell atlas of great ape forebrain development, and illuminate dynamic gene-regulatory features that are unique to humans.

DOI: 10.1038/s41586-019-1654-9

Source:https://www.nature.com/articles/s41586-019-1654-9

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html