Menezes Niels Alvaro, Peterson Kathryn Johanna, Guo Xiaogang, Castiglioni Veronica, Kalvisa Adrija, Filimonow Katarzyna, Schachter Karen, Schuh Christina Maria, Pasias Athanasios, Mariani Luca, Brickman Joshua Mark, Sedzinski Jakub, Ferretti Elisabetta
Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, 2200, Copenhagen N, Denmark.
Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), University of Copenhagen, 2200, Copenhagen N, Denmark.
Nat Commun. 2025 May 29;16(1):5000. doi: 10.1038/s41467-025-60348-6.
Stem cells hold promise in regenerative medicine as they have the potential to differentiate into a variety of specialized cell types. However, mechanisms underlying stem cell potency and lineage acquisition remain elusive. Epigenetic modifications and genome accessibility prime cellular feedback to signalling cues, influencing lineage differentiation outcomes. Deciphering how this epigenetic code influences the context-dependent response of pluripotent cells to differentiation cues will elucidate how mammalian tissue diversity is established. Using in vitro and in vivo models, we show that lineage-specific epigenetic signatures precede transcriptional activation of germ layer differentiation programs. We provide evidence that while distinct chromatin accessibility and methylome states prime extraembryonic mesodermal fate decisions, it is DNA methylation, and not chromatin accessibility that predetermines the fates of neuroectoderm, definitive endoderm and neuromesodermal lineages. This study establishes that epigenetic machinery fine-tunes epiblast potency, allowing context-specific spatiotemporal responses to promiscuously used signalling cues controlling organogenesis.
干细胞在再生医学领域具有广阔前景，因为它们有潜力分化为多种特化细胞类型。然而，干细胞潜能和谱系获得的潜在机制仍不清楚。表观遗传修饰和基因组可及性引发细胞对信号线索的反馈，影响谱系分化结果。解读这种表观遗传密码如何影响多能细胞对分化线索的上下文依赖性反应，将阐明哺乳动物组织多样性是如何建立的。利用体外和体内模型，我们发现谱系特异性表观遗传特征先于胚层分化程序的转录激活。我们提供的证据表明，虽然不同的染色质可及性和甲基化组状态引发了胚外中胚层命运的决定，但决定神经外胚层、定形内胚层和神经中胚层谱系命运的是DNA甲基化，而非染色质可及性。这项研究表明，表观遗传机制微调了上胚层的潜能，使机体能够对控制器官发生的、被随意利用的信号线索做出上下文特异性的时空反应。
