Deciphering lineage specification during early embryogenesis in mouse gastruloids using multilayered proteomics

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING
Suzan Stelloo, Maria Teresa Alejo-Vinogradova, Charlotte A.G.H. van Gelder, Dick W. Zijlmans, Marek J. van Oostrom, Juan Manuel Valverde, Lieke A. Lamers, Teja Rus, Paula Sobrevals Alcaraz, Tilman Schäfers, Cristina Furlan, Pascal W.T.C. Jansen, Marijke P.A. Baltissen, Katharina F. Sonnen, Boudewijn Burgering, Maarten A.F.M. Altelaar, Harmjan R. Vos, Michiel Vermeulen
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Abstract

Gastrulation is a critical stage in embryonic development during which the germ layers are established. Advances in sequencing technologies led to the identification of gene regulatory programs that control the emergence of the germ layers and their derivatives. However, proteome-based studies of early mammalian development are scarce. To overcome this, we utilized gastruloids and a multilayered mass spectrometry-based proteomics approach to investigate the global dynamics of (phospho) protein expression during gastruloid differentiation. Our findings revealed many proteins with temporal expression and unique expression profiles for each germ layer, which we also validated using single-cell proteomics technology. Additionally, we profiled enhancer interaction landscapes using P300 proximity labeling, which revealed numerous gastruloid-specific transcription factors and chromatin remodelers. Subsequent degron-based perturbations combined with single-cell RNA sequencing (scRNA-seq) identified a critical role for ZEB2 in mouse and human somitogenesis. Overall, this study provides a rich resource for developmental and synthetic biology communities endeavoring to understand mammalian embryogenesis.

Abstract Image

利用多层蛋白质组学破译小鼠胃肠早期胚胎发育过程中的血统规范
胚层形成是胚胎发育的关键阶段,在这一阶段胚层得以建立。随着测序技术的进步,人们发现了控制胚层及其衍生物出现的基因调控程序。然而,基于蛋白质组的哺乳动物早期发育研究却很少。为了克服这一问题,我们利用胃肠动物和基于多层质谱的蛋白质组学方法研究了胃肠动物分化过程中(磷酸)蛋白表达的整体动态。我们的发现揭示了许多蛋白质的时间表达和每个胚层独特的表达谱,我们还利用单细胞蛋白质组学技术对其进行了验证。此外,我们还利用 P300 接近标记技术分析了增强子相互作用图谱,发现了许多胃肠道特异性转录因子和染色质重塑因子。随后进行的基于去核糖体的扰动结合单细胞 RNA 测序(scRNA-seq)确定了 ZEB2 在小鼠和人类体细胞发生中的关键作用。总之,这项研究为致力于了解哺乳动物胚胎发生的发育生物学和合成生物学界提供了丰富的资源。
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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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