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  3. Single-Cell RNA-Seq Reveals Dynamic Early Embryonic-like Programs during Chemical Reprogramming

Single-Cell RNA-Seq Reveals Dynamic Early Embryonic-like Programs during Chemical Reprogramming

  • Cell Stem Cell. 2018 Jul 5;23(1):31-45.e7. doi: 10.1016/j.stem.2018.05.025.
Ting Zhao 1,  Yao Fu 2,  Jialiang Zhu 2,  Yifang Liu 3,  Qian Zhang 4,  Zexuan Yi 5,  Shi Chen 6,  Zhonggang Jiao 2,  Xiaochan Xu 7,  Junquan Xu 8,  Shuguang Duo 9,  Yun Bai 6,  Chao Tang 7,  Cheng Li 10,  Hongkui Deng 11
Affiliations

Affiliations

  • 1 Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100191, China; Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  • 2 Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100191, China.
  • 3 Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 4 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies and School of Life Sciences, Center for Statistical Science and Center for Bioinformatics, Peking University, Beijing 100871, China.
  • 5 Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100191, China; Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Peking University, Beijing 100871, China.
  • 6 Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100083, China.
  • 7 Center for Quantitative Biology and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
  • 8 CapitalBio Technology Corporation, Beijing 102206, China.
  • 9 Institute of Zoology, Chinese Academy Sciences, Beijing 100101, China.
  • 10 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies and School of Life Sciences, Center for Statistical Science and Center for Bioinformatics, Peking University, Beijing 100871, China. Electronic address: cheng_li@pku.edu.cn.
  • 11 Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100191, China; Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China. Electronic address: hongkui_deng@pku.edu.cn.
PMID: 29937202 DOI: 10.1016/j.stem.2018.05.025
Abstract

Chemical reprogramming provides a powerful platform for exploring the molecular dynamics that lead to pluripotency. Although previous studies have uncovered an intermediate extraembryonic endoderm (XEN)-like state during this process, the molecular underpinnings of pluripotency acquisition remain largely undefined. Here, we profile 36,199 single-cell transcriptomes at multiple time points throughout a highly efficient chemical reprogramming system using RNA-sequencing and reconstruct their progression trajectories. Through identifying sequential molecular events, we reveal that the dynamic early embryonic-like programs are key aspects of successful reprogramming from XEN-like state to pluripotency, including the concomitant transcriptomic signatures of two-cell (2C) embryonic-like and early pluripotency programs and the epigenetic signature of notable genome-wide DNA demethylation. Moreover, via enhancing the 2C-like program by fine-tuning chemical treatment, the reprogramming process is remarkably accelerated. Collectively, our findings offer a high-resolution dissection of cell fate dynamics during chemical reprogramming and shed LIGHT on mechanistic insights into the nature of induced pluripotency.

Keywords

2C-like program; CiPSC; XEN-like cell; Zscan4; chemical reprogramming; early embryonic-like programs; genome-wide hypomethylation; pluripotency; reprogramming trajectory; single-cell RNA-seq.

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