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Epigenetic and transcriptional regulations prime cell fate before division during human pluripotent stem cell differentiation

Author

Listed:
  • Pedro Madrigal

    (University of Cambridge
    Wellcome Genome Campus
    University of Cambridge
    European Bioinformatics Institute)

  • Siwei Deng

    (University of Oxford, Headington)

  • Yuliang Feng

    (University of Oxford, Headington)

  • Stefania Militi

    (University of Oxford, Headington)

  • Kim Jee Goh

    (University of Cambridge
    The Francis Crick Institute)

  • Reshma Nibhani

    (University of Oxford, Headington)

  • Rodrigo Grandy

    (University of Cambridge)

  • Anna Osnato

    (University of Cambridge)

  • Daniel Ortmann

    (University of Cambridge)

  • Stephanie Brown

    (University of Cambridge)

  • Siim Pauklin

    (University of Oxford, Headington)

Abstract

Stem cells undergo cellular division during their differentiation to produce daughter cells with a new cellular identity. However, the epigenetic events and molecular mechanisms occurring between consecutive cell divisions have been insufficiently studied due to technical limitations. Here, using the FUCCI reporter we developed a cell-cycle synchronised human pluripotent stem cell (hPSC) differentiation system for uncovering epigenome and transcriptome dynamics during the first two divisions leading to definitive endoderm. We observed that transcription of key differentiation markers occurs before cell division, while chromatin accessibility analyses revealed the early inhibition of alternative cell fates. We found that Activator protein-1 members controlled by p38/MAPK signalling are necessary for inducing endoderm while blocking cell fate shifting toward mesoderm, and that enhancers are rapidly established and decommissioned between different cell divisions. Our study has practical biomedical utility for producing hPSC-derived patient-specific cell types since p38/MAPK induction increased the differentiation efficiency of insulin-producing pancreatic beta-cells.

Suggested Citation

  • Pedro Madrigal & Siwei Deng & Yuliang Feng & Stefania Militi & Kim Jee Goh & Reshma Nibhani & Rodrigo Grandy & Anna Osnato & Daniel Ortmann & Stephanie Brown & Siim Pauklin, 2023. "Epigenetic and transcriptional regulations prime cell fate before division during human pluripotent stem cell differentiation," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36116-9
    DOI: 10.1038/s41467-023-36116-9
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