2. Academic Validation
  3. Cell cycle heterogeneity directs spontaneous 2C state entry and exit in mouse embryonic stem cells

Cell cycle heterogeneity directs spontaneous 2C state entry and exit in mouse embryonic stem cells

  • Stem Cell Reports. 2021 Nov 9;16(11):2659-2673. doi: 10.1016/j.stemcr.2021.09.003.
Yuqing Zhu 1,  Chen Cheng 2,  Lang Chen 2,  Li Zhang 2,  Hongru Pan 2,  Linxiao Hou 2,  Zhen Sun 2,  Ling Zhang 3,  Xudong Fu 4,  Kuan Yoow Chan 5,  Jin Zhang 6
Affiliations

Affiliations

  • 1 Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Hangzhou, Zhejiang, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, Zhejiang, China.
  • 2 Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Hangzhou, Zhejiang, China.
  • 3 Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Hangzhou, Zhejiang, China; Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China.
  • 4 Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Hangzhou, Zhejiang, China; Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 5 Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, Zhejiang, China.
  • 6 Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Hangzhou, Zhejiang, China; Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China; Center of Gene/Cell Engineering and Genome Medicine, Hangzhou, Zhejiang, China. Electronic address: zhgene@zju.edu.cn.
PMID: 34624246 DOI: 10.1016/j.stemcr.2021.09.003
Abstract

Mouse embryonic stem cells (ESCs) show cell-to-cell heterogeneity. A small number of two-cell-like cells (2CLCs) marked by endogenous retrovirus activation emerge spontaneously. The 2CLCs are unstable and they are prone to transiting back to the pluripotent state without extrinsic stimulus. To understand how this bidirectional transition takes place, we performed single-cell RNA Sequencing on isolated 2CLCs that underwent 2C-like state exit and re-entry, and revealed a step-by-step transitional process between 2C-like and pluripotent states. Mechanistically, we found that cell cycle played an important role in mediating these transitions by regulating assembly of the nucleolus and peri-nucleolar heterochromatin to influence 2C gene Dux expression. Collectively, our findings provide a roadmap of the 2C-like state entry and exit in ESCs and also a causal role of the cell cycle in promoting these transitions.

Keywords

2C-like cells; nucleolus; peri-nucleolar heterochromatin; single-cell RNA-seq.

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