Mechanistic study of 3D chromatin organization in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is malignant cancer with a high risk of recurrence and aggressive phenotype compared to other breast cancer subtypes. To date, although breast cancer studies mainly investigated genetic variations and the differential target gene expressions, how the 3D chromatin architectures are reorganized in TNBC has been poorly elucidated. Here, using in situ Hi-C, we characterized the 3D chromatin organization in cells representing five distinct subtypes of breast cancer (including TNBC) compared to normal cells. We found that the global and local 3D architectures are severely disrupted in breast cancer. In particular, TNBC cell line such as BT549 showed the most dramatic changes compared to normal cells. Importantly, we detected CTCF-dependent TNBC-susceptible loss/gain of 3D chromatin organization and found that these changes were strongly associated with perturbed chromatin accessibility and transcriptional dysregulations. In TNBC tissue, the 3D chromatin was also disorganized compared to normal tissues. We observed that perturbed local 3D architectures found in TNBC cells are partially conserved in TNBC tissues. Lastly, we discovered distinct tissue-specific chromatin loops by comparing normal and TNBC tissues. In this study, we elucidated the characteristic of 3D chromatin organization of breast cancer compared to normal cells/tissues at multi-scales and detected the associations between disrupted structures and various epigenetic features and transcriptomes. Collectively, our findings will provide important 3D chromatin structural features for TNBC diagnostic and therapeutic studies.