美国纪念斯隆-凯特琳癌症中心Lorenz Studer小组取得一项新突破。他们探明了全基因组CRISPR筛选发现Menin和SUZ12是人类发育时间的调节因子。这一研究成果发表在2025年9月2日出版的国际学术期刊《自然—细胞生物学》上。

在这里，课题组人员将人胚胎干细胞定向分化为神经外胚层，进行了全基因组CRISPR-Cas9敲除筛选，并表明表观遗传因子Menin和SUZ12调节了神经分化过程中PAX6的表达速度。Menin或SUZ12的遗传和药理学功能丧失通过改变H3K4me3和H3K27me3在二价启动子上的平衡来加速细胞命运的获得，从而启动关键的发育基因，在分化时更快地激活。小组进一步揭示了Menin和SUZ12在调节分化速度方面的协同作用。在确定的内胚层、心肌细胞和神经元分化范式中观察到加速效应，指出染色质二价是跨胚层和发育阶段时间的一般驱动因素。

据悉，不同物种的胚胎发育遵循一个保守的序列，但发育的速度是高度可变的，在人类中尤其缓慢。在干细胞模型中，物种特异性的发育时间在很大程度上得到了再现，这表明细胞具有内在的时钟。

附：英文原文

Title: Genome-wide CRISPR screen identifies Menin and SUZ12 as regulators of human developmental timing

Author: 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

Issue&Volume: 2025-09-02

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.

DOI: 10.1038/s41556-025-01751-5

Source: https://www.nature.com/articles/s41556-025-01751-5