两篇论文颠覆胚胎发育的科学共识

最近，加州大学圣地亚哥分校的生物工程师在《Genome Research》和《PNAS》发表的两项研究指出，小鼠胚胎在受精后的最早期阶段（此时胚胎只有两到四个细胞），就已经在考虑它们的细胞命运。这一发现可能会颠覆关于“胚胎细胞何时开始分化为细胞类型”的科学共识。

　　

生物通报道：最近，加州大学圣地亚哥分校的生物工程师发现，小鼠胚胎在受精后的最早期阶段（此时胚胎只有两到四个细胞），就已经在考虑它们的细胞命运。这一发现可能会颠覆关于“胚胎细胞何时开始分化为细胞类型”的科学共识。他们的研究，采用单细胞RNA测序，来研究小鼠基因组中的每个基因，相关研究结果发表在最近的《Genome Research》杂志。此外，该研究小组还在《PNAS》上发表论文，对胚胎发育精确阶段所收集的“时间进程”单细胞数据进行分析。

加州大学圣地亚哥分校Jacobs工程学院生物工程学教授Sheng Zhong称：“直到最近，我们才有一种技术，得以密切观察细胞。使用单细胞的RNA测序，我们能够在发育的多个阶段，测量小鼠基因组中的每个基因，以发现每个精确阶段的基因表达差异。”相关阅读：解读单细胞RNA-seq技术

研究结果揭示的细胞活性，可以让我们深入了解正常发育过程是在何处中止的，从而导致早期流产和出生缺陷。

研究人员发现，在两细胞和四细胞阶段，极少数基因彼此之间会发出明确的信号，这发生在精卵受精后的几天内，在胚胎植入子宫之前。在确定的基因当中，有几个基因属于Wnt信号通路，这个通路因其在细胞交流中的作用而众所周知。

直到现在，普通的看法一直认为，哺乳动物胚胎，在它们增殖到足够大的数字以形成子群之后，才开始分化为细胞类型。根据本文共同作者Fernando Biase和Xiaoyi Cao介绍，何时做出第一个细胞命运，是一个未解决的问题。对一个胚胎来说，首要的任务是，决定哪个细胞将开始形成胎儿，哪个细胞将会形成胎盘。

这项研究是由美国国立卫生研究院和美国畸形儿基金会资助。11月份，两项研究结果分别以“Cell fate inclination within 2-cell and 4-cell mouse embryos revealed by single-cell RNA sequencing”为题发表在《Genome Research》，以“Time-variant clustering model for understanding cell fate decisions”为题发表在《PNAS》杂志。

Zhong关于系统或网络生物学的研究，应用工程学原理来理解生物系统是如何发挥作用。例如，他们开发出某种分析方法，利用一个人的个人基因组和表观基因组，来预测个人的表型，指一个人的物理描述，从眼睛、头发颜色到健康状况和性情。表观基因组意指DNA中的化学物质，可调节基因表达且因人而异。用基因组和表观基因组来预测表型，是一个新兴的研究领域，科学家认为，这种研究可以为我们提供新的方法，来预测和治疗遗传性疾病。

（生物通：王英）

生物通推荐原文摘要：
Cell fate inclination within 2-cell and 4-cell mouse embryos revealed by single-cell RNA sequencing
Abstract：It remains an open question when and how the first cell fate decision is made in mammals. Using deep single-cell RNA-seq of matched sister blastomeres, we report highly reproducible inter-blastomere differences among 10 2-cell and five 4-cell mouse embryos. Inter-blastomere gene expression differences dominated between-embryo differences and noise, and were sufficient to cluster sister blastomeres into distinct groups. Dozens of protein-coding genes exhibited reproducible bimodal expression in sister blastomeres, which cannot be explained by random fluctuations. The protein expression of one gene out of four of these bimodal genes tested, Gadd45a, exhibited clear inter-blastomeric contrasts. We traced some of the bimodal mRNA expressions to embryonic genome activation, and others to blastomere-specific RNA depletion. Inter-blastomere differences created coexpression gene networks that were much stronger and larger than those that can possibly be created by random noise. The highly correlated gene pairs at the 4-cell stage overlapped with those showing the same directions of differential expression between inner cell mass (ICM) and trophectoderm (TE). These data substantiate the hypothesis of inter-blastomere differences in 2- and 4-cell mouse embryos, and associate these differences with ICM/TE differences.

Time-variant clustering model for understanding cell fate decisions
Abstract：Both spatial characteristics and temporal features are often the subjects of concern in physical, social, and biological studies. This work tackles the clustering problems for time course data in which the cluster number and clustering structure change with respect to time, dubbed time-variant clustering. We developed a hierarchical model that simultaneously clusters the objects at every time point and describes the relationships of the clusters between time points. The hidden layer of this model is a generalized form of branching processes. A reversible-jump Markov Chain Monte Carlo method was implemented for model inference, and a feature selection procedure was developed. We applied this method to explore an open question in preimplantation embryonic development. Our analyses using single-cell gene expression data suggested that the earliest cell fate decision could start at the 4-cell stage in mice, earlier than the commonly thought 8- to 16-cell stage. These results together with independent experimental data from single-cell RNA-seq provided support against a prevailing hypothesis in mammalian development.