Genome-wide CRISPR screen identifies Menin and SUZ12 as regulators of human developmental timing Journal Article

   


Authors: Xu, N.; Cho, H. S.; Hackland, J. O. S.; Benito-Kwiecinski, S.; Saurat, N.; Harschnitz, O.; Russo, M. V.; Garippa, R.; Ciceri, G.; Studer, L.
Article Title: Genome-wide CRISPR screen identifies Menin and SUZ12 as regulators of human developmental timing
Abstract: Embryonic development follows a conserved sequence of events across species, yet the pace of development is highly variable and particularly slow in humans. Species-specific developmental timing is largely recapitulated in stem cell models, suggesting a cell-intrinsic clock. Here we use directed differentiation of human embryonic stem cells into neuroectoderm to perform a whole-genome CRISPR-Cas9 knockout screen and show that the epigenetic factors Menin and SUZ12 modulate the speed of PAX6 expression during neural differentiation. Genetic and pharmacological loss-of-function of Menin or SUZ12 accelerate cell fate acquisition by shifting the balance of H3K4me3 and H3K27me3 at bivalent promoters, thereby priming key developmental genes for faster activation upon differentiation. We further reveal a synergistic interaction of Menin and SUZ12 in modulating differentiation speed. The acceleration effects were observed in definitive endoderm, cardiomyocyte and neuronal differentiation paradigms, pointing to chromatin bivalency as a general driver of timing across germ layers and developmental stages.
Keywords: chromatin; pluripotent; differentiation; expression; embryonic stem-cells; ezh2; polycomb; human es; histone methyltransferase complex; bivalent promoters
Journal Title: Nature Cell Biology
Volume: 27
Issue: 9
ISSN: 1465-7392
Publisher: Nature Publishing Group  
Publication status: Published
Date Published: 2025-09-01
Start Page: 1411
End Page: 1421
Language: English
ACCESSION: WOS:001562257200001
DOI: 10.1038/s41556-025-01751-5
PROVIDER: wos
PMCID: PMC12431854
PUBMED: 40897805
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Gabriele Ciceri and Lorenz Studer -- Source: Wos
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MSK Authors
  1. Lorenz Studer
    226 Studer
  2. Ralph James Garippa
    33 Garippa
  3. Hyein Cho
    13 Cho
  4. Nathalie Gael Saurat
    8 Saurat
  5. Oliver Harschnitz
    12 Harschnitz
  6. Gabriele Ciceri
    16 Ciceri
  7. James Owen Spencer Hackland
    4 Hackland
  8. Marco Vincenzo Russo
    8 Russo
  9. Silvia Kima Benito Kwiecinski
    2 Benito Kwiecinski
  10. Nan Xu
    4 Xu
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