全基因组CRISPR筛选确定Menin和SUZ12为人类发育时间的调节因子。
Genome-wide CRISPR screen identifies Menin and SUZ12 as regulators of human developmental timing.
作者信息
Xu Nan, Cho Hyein S, Hackland James O S, Benito-Kwiecinski Silvia, Saurat Nathalie, Harschnitz Oliver, Russo Marco Vincenzo, Garippa Ralph, Ciceri Gabriele, Studer Lorenz
机构信息
The Center for Stem Cell Biology and Developmental Biology program; Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, New York, NY, USA.
出版信息
Nat Cell Biol. 2025 Sep 2. doi: 10.1038/s41556-025-01751-5.
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.
胚胎发育在物种间遵循一系列保守的事件顺序,然而发育速度在不同物种间差异很大,在人类中尤其缓慢。物种特异性的发育时间在很大程度上在干细胞模型中得以重现,这表明存在一种细胞内在时钟。在这里,我们利用人类胚胎干细胞定向分化为神经外胚层来进行全基因组CRISPR-Cas9敲除筛选,并表明表观遗传因子Menin和SUZ12在神经分化过程中调节PAX6表达的速度。Menin或SUZ12的基因和药理学功能丧失通过改变二价启动子处H3K4me3和H3K27me3的平衡来加速细胞命运的获得,从而使关键发育基因在分化时更快地被激活。我们进一步揭示了Menin和SUZ12在调节分化速度方面的协同相互作用。在确定的内胚层、心肌细胞和神经元分化模式中都观察到了加速效应,这表明染色质双价性是跨胚层和发育阶段的时间调控的一般驱动因素。