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STEM CELLS AND REGENERATION
Dynamic transcriptional symmetry-breaking in pre-implantation mammalian embryo development revealed by single-cell RNA-seq
Junchao Shi, Qi Chen, Xin Li, Xiudeng Zheng, Ying Zhang, Jie Qiao, Fuchou Tang, Yi Tao, Qi Zhou, Enkui Duan
Development 2015 142: 3468-3477; doi: 10.1242/dev.123950
Junchao Shi
1State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China
2University of Chinese Academy of Sciences, 100049 Beijing, China
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Qi Chen
1State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China
3Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
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  • For correspondence: cqi@medicine.nevada.edu yitao@ioz.ac.cn qzhou@ioz.ac.cn duane@ioz.ac.cn
Xin Li
1State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China
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Xiudeng Zheng
1State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China
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Ying Zhang
1State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China
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Jie Qiao
4Biodynamic Optical Imaging Center and Center for Reproductive Medicine, College of Life Sciences, Third Hospital, Peking University, 100871 Beijing, China
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Fuchou Tang
4Biodynamic Optical Imaging Center and Center for Reproductive Medicine, College of Life Sciences, Third Hospital, Peking University, 100871 Beijing, China
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Yi Tao
1State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China
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  • For correspondence: cqi@medicine.nevada.edu yitao@ioz.ac.cn qzhou@ioz.ac.cn duane@ioz.ac.cn
Qi Zhou
1State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China
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  • For correspondence: cqi@medicine.nevada.edu yitao@ioz.ac.cn qzhou@ioz.ac.cn duane@ioz.ac.cn
Enkui Duan
1State Key Laboratory of Stem Cell and Reproductive Biology, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China
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  • For correspondence: cqi@medicine.nevada.edu yitao@ioz.ac.cn qzhou@ioz.ac.cn duane@ioz.ac.cn
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    Fig. 1.

    Expression biases in two-cell blastomeres approximately follow a binomial distribution pattern. (A) Theoretical curve of binomial distribution from a homogenous ancestor, with thresholds of differential distribution of 10%, 15% and 20% of putative molecules. (B) Scatter plot comparison analysis of single-blastomere transcriptomes of two-cell mouse blastomeres. R, correlation coefficient. (C,D) Transcript counts in two-cell blastomeres were tested against the theoretical curve (for 20% unequal distribution) under binominal partition and a scale of 1000 counts (C) and 100 counts (D). Error bars indicate s.e.m., with average values from four independent embryos. Correlation coefficient R represents the fitness of data to the theoretical curve.

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    Fig. 2.

    Zygotic transcriptional activation elevates initial blastomere-to-blastomere biases. (A) Illustration of the strategy to analyze separately the two sources of blastomere-to-blastomere heterogeneity, namely partitioning errors and transcriptional noise, in an early-to-late two-cell embryo in a stage-specific manner. (B) Blastomere-to-blastomere expression noise calculated with a previously published formula using a single-blastomere transcriptome from an early-to-late two-cell embryo as well as using technical repeats of RNA-seq data from early blastomeres (Eqn 2 in Materials and Methods). (C) The extent of blastomere-to-blastomere gene expression asymmetry is represented by Ehigher/Elower. If the gene expression in the two blastomeres is more similar, the value of Ehigher/Elower will be closer to 1. ***P<0.001; different letters indicate statistical difference, P<0.01; same letters indicate P>0.05; one-way ANOVA.

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    Fig. 3.

    Multiplied partitioning errors and elevated overall blastomere-to-blastomere biases during the two- to 16-cell stages. (A) Illustration showing that multiplied partitioning errors at each cleavage division drive the continuously increasing cell-to-cell bias, each time creating one daughter cell bearing a higher quantity of a specific substance and another with a lower quantity of that substance (Eqns 3-5 in Materials and Methods). The graph shows the amplification effect of a small bias (10% co-efficiency) during the first rounds of cleavage division; G0-3 indicates generations 0-3. (B) Single-blastomere RNA-seq and blastomere-to-blastomere expression noise in two- to eight-cell embryos in both mouse and human. Each dot represents a comparison of two blastomeres within one embryo. Datasets from mouse (Deng et al., 2014) and human (Yan et al., 2013) were used for the calculations. Different letters indicate statistical difference, P<0.01; same letters indicate P>0.05; one-way ANOVA.

  • Fig. 4.
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    Fig. 4.

    Trends of transcriptional asymmetry during the two- to 16-cell embryo stages reveals monostable and bistable patterns. (A-D) The trends of blastomere-to-blastomere asymmetry for genes with high expression level (top 20%) and strong bias (top 20%) at the two-cell (A), four-cell (B), eight-cell (C) and 16-cell (D) stages. (E) The expression asymmetries of Tubb2c, Carm1 and Pou5f1 were analyzed using single-blastomere expression profiles from two-cell to 16-cell embryo stages in mouse. The average expression level of each gene in each embryo is normalized to 1, and the relative expression level of each gene in each blastomere is shown using different shapes/colors, as illustrated. The dispersion degree along the y-axis can be directly visualized in each embryo and represents the overall extent of expression asymmetry between different blastomeres. Each dot represents the relative value of each blastomere to the average RPKM of all blastomeres within one embryo. (F,G) Dynamics of single gene expression systems with negative/positive feedback regulation. The change of protein X over time (dX/dt) can be described by a differential equation which is synthesis rate S+ minus degradation rate S−. The top two panels are the plot of the functions S+ and S− within the same graph. The lower two panels illustrate the corresponding potential function of the system. From these graphs, there are one (F) or three (G) intersection points, indicating the steady states in which dX/dt is equal to 0. The directions of the arrows indicate the movement towards equilibrium. If two arrows move away from each other, this represents an unstable steady state. Therefore, a single gene expression system with negative feedback regulation (F) has only one stable steady states and a single gene expression system with positive feedback regulation (G) has two stable steady states: one in which the level of X is low and one in which the level of X is high; the system could shift into either of these two states from the unstable point.

  • Fig. 5.
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    Fig. 5.

    Cleavage history and de novo transcription contribute to the relative ratio of opposing lineage specifiers. (A) Illustration of the tilted ratio of two substances as a result of partitioning error. (B) Colors indicate the probability of tilting an initial ratio (10% threshold) of a pair of lineage specifiers with counteracting functions (Eqn 6 in Materials and Methods). (C) The stage-specific expression level (RPKM value) of Carm1 and Cdx2 during the one- to eight-cell embryo stages. n=3 for each column. Data used to generate these columns are derived from a previous publication (Xie et al., 2010). (D,E) The RPKM values of Carm1 and Cdx2 in each eight-cell blastomere examined from mouse (D) and human (E) embryos. (F,G) The relative ratios of Carm1 and Cdx2 in different eight-cell blastomeres form distinct lineage strengths in both mouse (F) and human (G) embryos. The graphs in F and G were generated from the raw numbers in D and E, respectively. Previously published mouse (Deng et al., 2014) and human (Yan et al., 2013) datasets were used to generate the table and figure.

  • Fig. 6.
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    Fig. 6.

    A symmetry-breaking and lineage-competition model involving both random segregation and transcriptional regulation. The partitioning error at each cleavage division and the transcriptional circuits along embryo development are two major sources for initial generation and subsequent fine-tuning of blastomere-to-blastomere heterogeneity. These two factors also change the initial ratio of opposing lineage specifiers in mother or daughter blastomeres, thus changing the initial trajectory of lineage fate. The changes in color density represent the gradually reinforced lineage strength of either side. Note that an undecided impression could be observed at a static time point, representing a snapshot of the continuous lineage competition. Clues to cell fate bifurcation have been developed by the ratios of opposing lineage specifiers, with the wax and wane of either side (illustrated by different colors in each sphere) finally leading to the dichotomy of cell fate.

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Keywords

  • Transcriptional symmetry-breaking
  • Pre-implantation embryo development
  • Lineage divergence
  • Monostable model
  • Bistable model

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STEM CELLS AND REGENERATION
Dynamic transcriptional symmetry-breaking in pre-implantation mammalian embryo development revealed by single-cell RNA-seq
Junchao Shi, Qi Chen, Xin Li, Xiudeng Zheng, Ying Zhang, Jie Qiao, Fuchou Tang, Yi Tao, Qi Zhou, Enkui Duan
Development 2015 142: 3468-3477; doi: 10.1242/dev.123950
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STEM CELLS AND REGENERATION
Dynamic transcriptional symmetry-breaking in pre-implantation mammalian embryo development revealed by single-cell RNA-seq
Junchao Shi, Qi Chen, Xin Li, Xiudeng Zheng, Ying Zhang, Jie Qiao, Fuchou Tang, Yi Tao, Qi Zhou, Enkui Duan
Development 2015 142: 3468-3477; doi: 10.1242/dev.123950

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