Hölzenspies Jurriaan Jochem, Sengupta Dipta, Bickmore Wendy Anne, Brickman Joshua Mark, Illingworth Robert Scott
Novo Nordisk Foundation Center for Stem Cell Medicine-reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom.
PLoS Genet. 2025 Jan 30;21(1):e1011584. doi: 10.1371/journal.pgen.1011584. eCollection 2025 Jan.
The genetic circuitry that encodes the developmental programme of mammals is regulated by transcription factors and chromatin modifiers. During early gestation, the three embryonic germ layers are established in a process termed gastrulation. The impact of deleterious mutations in chromatin modifiers such as the polycomb proteins manifests during gastrulation, leading to early developmental failure and lethality in mouse models. Embryonic stem cells have provided key insights into the molecular function of polycomb proteins, but it is impossible to fully appreciate the role of these epigenetic factors in development, or how development is perturbed due to their deficiency, in the steady-state. To address this, we have employed a tractable embryonic stem cell differentiation system to model primitive streak formation and early gastrulation. Using this approach, we find that loss of the repressive polycomb mark H3K27me3 is delayed relative to transcriptional activation, indicating a subordinate rather than instructive role in gene repression. Despite this, chemical inhibition of polycomb enhanced endodermal differentiation efficiency, but did so at the cost of lineage fidelity. These findings highlight the importance of the polycomb system in stabilising the developmental transcriptional response and, in so doing, in shoring up cellular specification.
编码哺乳动物发育程序的遗传回路受转录因子和染色质修饰因子调控。在妊娠早期，三个胚胎胚层在一个称为原肠胚形成的过程中建立。染色质修饰因子（如多梳蛋白）中的有害突变的影响在原肠胚形成过程中显现，导致小鼠模型早期发育失败和死亡。胚胎干细胞为多梳蛋白的分子功能提供了关键见解，但在稳态下，不可能充分理解这些表观遗传因子在发育中的作用，也无法了解由于它们的缺陷发育是如何受到干扰的。为了解决这个问题，我们采用了一种易于处理的胚胎干细胞分化系统来模拟原条形成和早期原肠胚形成。使用这种方法，我们发现抑制性多梳标记H3K27me3的丢失相对于转录激活有所延迟，表明其在基因抑制中起从属而非指导作用。尽管如此，多梳的化学抑制提高了内胚层分化效率，但代价是谱系保真度。这些发现突出了多梳系统在稳定发育转录反应以及由此巩固细胞特化方面的重要性。
