Yingying Chen, Fengxiang Tan, Qing Fang, Lin Zhang, Jiaoyang Liao, Penglei Shen, Yun Qian, Mingzhu Wen, Rui Song, Yonggao Fu, He Jax Xu, Ran Wang, Cheng Li, Zhen Shao, Jinsong Li, Naihe Jing, Xianfa Yang
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引用次数: 0
Abstract
The regulatory mechanisms governing cell fate determination, particularly lineage diversification during mammalian embryonic development, remain poorly understood with in-depth regulatory paradigms yet to be fully elucidated. Here, leveraging the epigenetic landscape of mouse gastrula, p-Enh is identified, an enhancer located within the first intron of Cdx2 and epigenetically pre-marked in the primitive streak region, as a pivotal regulator for posterior tissue development in mouse embryos. Morphological and single-cell transcriptomic analyses confirmed embryonic lethality phenotype with disrupted posterior tissue development trajectories in p-Enh-KO embryos. Molecularly, apart from regulating the neighboring coding-gene Cdx2 in cis, the findings suggest that p-Enh also modulates the global transcriptome and epigenomic landscape, which might through the transient production of eRNA in trans. Further investigation revealed p-Enh-derived eRNAs participate in the regulatory cascades of TGF-β signaling by directly interacting with SMAD4 protein. Combinatorial modulation of TGF-β signaling and p-Enh-eRNA abundance can largely rescue the posterior development deficiency in in vitro gastruloids through a Cdx2-independent mechanism. Thus, a potential model is proposed in which the broadly distributed p-Enh transcripts within the nucleus can serve as essential cross-modular coordinators, priming the posterior development of mouse embryo.
调控细胞命运决定的机制,特别是哺乳动物胚胎发育过程中的谱系多样化,仍然知之甚少,深入的调控范式尚未完全阐明。在这里,利用小鼠原肠胚的表观遗传格局,发现了p-Enh,一个位于Cdx2的第一个内含子内的增强子,在原始条纹区被表观遗传预先标记,是小鼠胚胎后组织发育的关键调节因子。形态学和单细胞转录组学分析证实了p- en - ko胚胎的胚胎致死性表型与后组织发育轨迹的破坏。从分子上看,p-Enh除了在顺式中调节邻近的编码基因Cdx2外,还可能通过在反式中瞬时产生eRNA来调节全局转录组和表观基因组格局。进一步的研究发现,p- enh衍生的erna通过直接与SMAD4蛋白相互作用参与TGF-β信号的调控级联反应。TGF-β信号和p-Enh-eRNA丰度的组合调节可以通过cdx2不依赖的机制在很大程度上挽救体外类胃原体的后发育缺陷。因此,提出了一个潜在的模型,其中广泛分布在细胞核内的p-Enh转录本可以作为必要的交叉模块协调者,启动小鼠胚胎的后发育。
期刊介绍:
Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.