2. Academic Validation
  3. Nuclear receptor-SINE B1 network modulates expanded pluripotency in blastoids and blastocysts

Nuclear receptor-SINE B1 network modulates expanded pluripotency in blastoids and blastocysts

  • Nat Commun. 2024 Nov 19;15(1):10011. doi: 10.1038/s41467-024-54381-0.
Ka Wai Wong # 1,  Yingying Zeng # 1 2,  Edison Tay 1,  Jia Hao Jackie Teo 1,  Nadia Omega Cipta 1,  Kiyofumi Hamashima 1,  Yao Yi 1,  Haijun Liu 3,  Tushar Warrier 1,  Minh T N Le 4 5 6,  Soon Chye Ng 3 7 8,  Qi-Jing Li 6 9,  Hu Li 10,  Yuin-Han Loh 11 12 13 14 15
Affiliations

Affiliations

  • 1 Cell Fate Engineering and Therapeutics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore.
  • 2 School of Biological Sciences, Nanyang Technological University, Singapore, Republic of Singapore.
  • 3 Endangered Species Conservation via Assisted Reproduction (ESCAR) Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore.
  • 4 Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
  • 5 Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
  • 6 Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore.
  • 7 Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
  • 8 Sincere Healthcare Group, Singapore, Republic of Singapore.
  • 9 Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore, 138648, Republic of Singapore.
  • 10 Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
  • 11 Cell Fate Engineering and Therapeutics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore. yhloh@imcb.a-star.edu.sg.
  • 12 Endangered Species Conservation via Assisted Reproduction (ESCAR) Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore. yhloh@imcb.a-star.edu.sg.
  • 13 Department of Biological Sciences, National University of Singapore, Singapore, Republic of Singapore. yhloh@imcb.a-star.edu.sg.
  • 14 NUS Graduate School's Integrative Sciences and Engineering Programme, National University of Singapore, Singapore, Republic of Singapore. yhloh@imcb.a-star.edu.sg.
  • 15 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore. yhloh@imcb.a-star.edu.sg.
  • # Contributed equally.
PMID: 39562549 DOI: 10.1038/s41467-024-54381-0
Abstract

Embryonic stem cells possess the remarkable ability to self-organize into blastocyst-like structures upon induction. These stem cell-based embryo models serve as invaluable platforms for studying embryogenesis and therapeutic developments. Nevertheless, the specific intrinsic regulators that govern this potential for blastoid formation remain unknown. Here we demonstrate an intrinsic program that plays a crucial role in both blastoids and blastocysts across multiple species. We first establish metrics for grading the resemblance of blastoids to mouse blastocysts, and identify the differential activation of gene regulons involved in lineage specification among various blastoid grades. Notably, abrogation of nuclear receptor subfamily 1, group H, member 2 (Nr1h2) drastically reduces blastoid formation. Nr1h2 activation alone is sufficient to rewire conventional ESC into a distinct pluripotency state, enabling them to form blastoids with enhanced implantation capacity in the uterus and contribute to both embryonic and extraembryonic lineages in vivo. Through integrative multi-omics analyses, we uncover the broad regulatory role of Nr1h2 in the transcriptome, chromatin accessibility and epigenome, targeting genes associated with embryonic lineage and the transposable element SINE-B1. The Nr1h2-centred intrinsic program governs and drives the development of both blastoids and early embryos.

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