3D Genome Architecture in Stem Cell Lineage Commitment: from Structural Organization to Precision Regulation

Yanchi He, Wenrui Li, Lin Li, Ying Yang, Yutong Lu, Yufei Pan, Qing Wang, Yuqiang Sun, Yuxuan Xie, Mingyue Wu, Peng Luo, Wansu Sun, Hengguo Zhang
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Abstract

Stem cell lineage commitment is governed by intricate interactions between epigenetic mechanisms and 3D genome organization. Traditional linear epigenetics, including DNA methylation and histone modifications, cannot fully elucidate the complex spatiotemporal regulation of gene expression. Recent advances in spatial genomics technologies, such as high-throughput chromosome conformation capture (Hi-C), single-cell Hi-C, and Chromatin immunoprecipitation combined with Hi-C (Hi-ChIP), have provided unprecedented insights into genome architecture, revealing key structural units like chromatin compartments, topologically associating domains (TADs), and chromatin loops. These structures dynamically reorganize during differentiation, influencing transcriptional accessibility and lineage-specific gene activation. Additionally, liquid-liquid phase separation (LLPS)-mediated transcriptional condensates, such as transcription factories and super-enhancers, have emerged as essential regulators of gene expression patterns during cell fate transitions. The integration of multiomics data and artificial intelligence-driven predictive modeling further enhances the understanding of these regulatory networks. Despite ongoing technical challenges, including limitations in resolution, data complexity, and causal inference, recent advances continue to push the field forward. Engineered interventions such as CRISPR-based spatial genome editing and AI-powered computational platforms hold great promise for translating structural insights into targeted therapeutic strategies in regenerative medicine.

Abstract Image

干细胞谱系承诺中的三维基因组结构:从结构组织到精确调节
干细胞谱系承诺是由表观遗传机制和三维基因组组织之间复杂的相互作用所控制的。传统的线性表观遗传学,包括DNA甲基化和组蛋白修饰,不能完全阐明基因表达的复杂时空调控。空间基因组学技术的最新进展,如高通量染色体构象捕获(Hi-C)、单细胞Hi-C和染色质免疫沉淀结合Hi-C (Hi-ChIP),为基因组结构提供了前所未有的见解,揭示了染色质室、拓扑相关结构域(TADs)和染色质环等关键结构单元。这些结构在分化过程中动态重组,影响转录可及性和谱系特异性基因激活。此外,液-液相分离(LLPS)介导的转录凝聚物,如转录工厂和超级增强子,已经成为细胞命运转变过程中基因表达模式的重要调节因子。多组学数据和人工智能驱动的预测建模的集成进一步增强了对这些调节网络的理解。尽管存在技术挑战,包括分辨率、数据复杂性和因果推理方面的限制,但最近的进展继续推动该领域向前发展。基于crispr的空间基因组编辑和人工智能驱动的计算平台等工程干预措施有望将结构见解转化为再生医学的靶向治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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