Single-cell analysis of bidirectional reprogramming between early embryonic states identify mechanisms of differential lineage plasticities in mice
Two distinct lineages, pluripotent epiblast (EPI) and primitive (extra-embryonic) endoderm (PrE), arise from common inner cell mass (ICM) progenitors in mammalian embryos. To study how these sister identities are forged, we leveraged mouse embryonic stem (ES) cells and extra-embryonic endoderm (XEN) stem cells-in vitro counterparts of the EPI and PrE. Bidirectional reprogramming between ES and XEN coupled with single-cell RNA and ATAC-seq analyses showed distinct rates, efficiencies, and trajectories of state conversions, identifying drivers and roadblocks of reciprocal conversions. While GATA4-mediated ES-to-iXEN conversion was rapid and nearly deterministic, OCT4-, KLF4-, and SOX2-induced XEN-to-induced pluripotent stem (iPS) reprogramming progressed with diminished efficiency and kinetics. A dominant PrE transcriptional program, safeguarded by GATA4, alongside elevated chromatin accessibility and reduced DNA methylation of the EPI underscored the differential plasticities of the two states. Mapping in vitro to embryo trajectories tracked reprogramming cells in either direction along EPI and PrE in vivo states, without transitioning through the ICM.
Authors
- Alexander Polyzos (ORCID: https://orcid.org/0000-0002-2509-9698)
- Anna‐Katerina Hadjantonakis (ORCID: https://orcid.org/0000-0002-7580-5124)
- Effie Apostolou (ORCID: https://orcid.org/0000-0002-8111-0863)
- Vidur Garg (ORCID: https://orcid.org/0000-0001-9443-0359)
- MiHyun Jang (ORCID: https://orcid.org/0000-0001-5638-2237)
- Eralda Salataj (ORCID: https://orcid.org/0000-0001-8661-1686)
- Roshan Sharma (ORCID: https://orcid.org/0000-0001-9886-009X)
- Dylan Murphy (ORCID: https://orcid.org/0000-0002-4368-8402)
- Ying-Yi Kuo (ORCID: https://orcid.org/0000-0002-1962-5559)
- Dana Pe’er (ORCID: https://orcid.org/0000-0002-9259-8817)
- Manu Setty (ORCID: https://orcid.org/0000-0002-0344-2627)
- Sonja Nowotschin (ORCID: https://orcid.org/0000-0002-2646-8598)
- Yang Yang (ORCID: https://orcid.org/0000-0002-0844-7929)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Cornell University (US)
- Kettering University (US)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- Developmental Cell
- Published
- 2024-12-26
- DOI
- https://doi.org/10.1016/j.devcel.2024.11.022
- Citations
- 2
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 0.47
Funders
- Memorial Sloan-Kettering Cancer Center
- Cycle for Survival
- National Institutes of Health
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases