類器官體單細胞測序揭示人類大腦發育特徵
作者：
小柯機器人發布時間：2019/10/17 14:17:36
德國馬克斯·普朗克進化人類學研究所J. Gray Camp、Barbara Treutlein和Zhisong He等研究人員合作繪製了大腦類器官體的單細胞基因組圖譜，從而揭示了人類特異的大腦發育特徵。該項研究成果2019年10月16日在線發表於國際學術期刊《自然》。
研究人員使用單細胞轉錄組學和染色質可及性測序分析了幹細胞來源的腦類器官體，以研究特定於人類的基因調節變化。
研究人員首先分析了人類全腦器官形成過程中從多能性到神經外胚層和神經上皮階段的細胞組成，並重建了分化軌跡，然後在背側和腹側前腦、中腦和後腦區域內分化為神經元命運。來自不同iPSC品系類器官的大腦區域組成各不相同，但是區域基因表達模式在各個個體之間仍可大致再現。研究人員分析了黑猩猩和獼猴的大腦類器官體，發現與其他兩個靈長類動物相比，人類神經元的發育速度較慢。使用分化路徑的擬時態比對，研究人員發現人類特異性基因表達沿皮質的祖細胞到神經元譜系解析為不同的細胞狀態。染色質的可及性在皮層發育過程中是動態的，研究人員發現人與黑猩猩之間可及性的差異與人特異性基因表達和遺傳變化有關。
最後，研究人員使用單核RNA測序分析繪製了成年人前額葉皮層中人特異性的表達圖，並確定了成年後持續存在的發育差異以及僅在成年大腦中發生的細胞狀態特異性變化。這些數據提供了大猿前腦發育的時序細胞圖譜，並闡明了人類獨有的動態基因調控功能。
據悉，自從人類脫離黑猩猩和其他大猿以來，人類的大腦發生了巨大變化。但是，導致這種差異的遺傳和發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