PDF(Pubmed)
Abstract：
Advances in chromatin mapping have exposed the complex chromatin hierarchical organization in mammals, including topologically associating domains (TADs) and their substructures, yet the functional implications of this hierarchy in gene regulation and disease progression are not fully elucidated. Our study delves into the phenomenon of shared TAD boundaries, which are pivotal in maintaining the hierarchical chromatin structure and regulating gene activity. By integrating high-resolution Hi-C data, chromatin accessibility, and DNA double-strand breaks (DSBs) data from various cell lines, we systematically explore the complex regulatory landscape at high-level TAD boundaries. Our findings indicate that these boundaries are not only key architectural elements but also vibrant hubs, enriched with functionally crucial genes and complex transcription factor binding site-clustered regions. Moreover, they exhibit a pronounced enrichment of DSBs, suggesting a nuanced interplay between transcriptional regulation and genomic stability. Our research provides novel insights into the intricate relationship between the 3D genome structure, gene regulation, and DNA repair mechanisms, highlighting the role of shared TAD boundaries in maintaining genomic integrity and resilience against perturbations. The implications of our findings extend to understanding the complexities of genomic diseases and open new avenues for therapeutic interventions targeting the structural and functional integrity of TAD boundaries.
摘要：
染色质定位的进展揭示了哺乳动物复杂的染色质分层组织，包括拓扑关联域(TAD)及其子结构，然而，这种层次结构在基因调控和疾病进展中的功能意义尚未完全阐明。我们的研究深入研究了共享TAD边界的现象，这对于维持分级染色质结构和调节基因活性至关重要。通过集成高分辨率Hi-C数据，染色质可及性，和来自各种细胞系的DNA双链断裂（DSB）数据，我们系统地探索高层TAD边界的复杂监管格局。我们的研究结果表明，这些边界不仅是关键的建筑元素，而且是充满活力的枢纽，富含功能关键基因和复杂的转录因子结合位点聚集区。此外，它们表现出明显的DSB富集，这表明转录调控和基因组稳定性之间存在微妙的相互作用。我们的研究为3D基因组结构之间的复杂关系提供了新的见解，基因调控，和DNA修复机制，强调共享TAD边界在维持基因组完整性和抗扰动弹性方面的作用。我们的发现的意义扩展到理解基因组疾病的复杂性，并为针对TAD边界的结构和功能完整性的治疗干预开辟了新的途径。
