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.　　©　2024　The　Author(s).