Schröder Chiara M, Zissel Lea, Mersiowsky Sophie-Luise, Tekman Mehmet, Probst Simone, Schüle Katrin M, Preissl Sebastian, Schilling Oliver, Timmers H Th Marc, Arnold Sebastian J
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
Dev Cell. 2025 Mar 10;60(5):735-748.e5. doi: 10.1016/j.devcel.2024.11.014. Epub 2024 Dec 10.
Mammalian pluripotent cells first segregate into neuroectoderm (NE), or mesoderm and endoderm (ME), characterized by lineage-specific transcriptional programs and chromatin states. To date, the relationship between transcription factor activities and dynamic chromatin changes that guide cell specification remains ill-defined. In this study, we employ mouse embryonic stem cell differentiation toward ME lineages to reveal crucial roles of the Tbx factor Eomes to globally establish ME enhancer accessibility as the prerequisite for ME lineage competence and ME-specific gene expression. EOMES cooperates with the SWItch/sucrose non-fermentable (SWI/SNF) complex to drive chromatin rewiring that is essential to overcome default NE differentiation, which is favored by asymmetries in chromatin accessibility at pluripotent state. Following global ME enhancer remodeling, ME-specific gene transcription is controlled by additional signals such as Wnt and transforming growth factor β (TGF-β)/NODAL, as a second layer of gene expression regulation, which can be mechanistically separated from initial chromatin remodeling activities.
哺乳动物多能细胞首先分化为神经外胚层（NE），或中胚层和内胚层（ME），其特征是具有谱系特异性转录程序和染色质状态。迄今为止，转录因子活性与指导细胞分化的动态染色质变化之间的关系仍不明确。在本研究中，我们利用小鼠胚胎干细胞向ME谱系分化，揭示了Tbx因子Eomes在全局建立ME增强子可及性方面的关键作用，这是ME谱系能力和ME特异性基因表达的先决条件。EOMES与SWItch/蔗糖非发酵（SWI/SNF）复合物协同作用，驱动染色质重塑，这对于克服默认的NE分化至关重要，而默认的NE分化在多能状态下受染色质可及性不对称的影响。在全局ME增强子重塑之后，ME特异性基因转录由诸如Wnt和转化生长因子β（TGF-β）/NODAL等额外信号控制，作为基因表达调控的第二层，这在机制上可与初始染色质重塑活动分开。
