期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：36
DOI：10.1073/pnas.2203452119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
During cancer progression, cells must adapt to facilitate invasion through stroma and subsequent metastatic growth in a distal niche. This adaption necessitates a great deal of plasticity, and there is evidence that epigenetic mechanisms govern these processes. While long-range chromatin interactions are key for proper genome organization and control of transcription, it is unclear whether reprogramming of three-dimensional chromatin architecture is important for mediating tumor progression. Here, we reveal that a common chromosomal aberration across cancers, CCCTC-binding factor (CTCF) copy number loss, potentiates cell invasion by reorganizing chromatin contacts at the level of sub–topologically associated domain (subTAD) interactions. We observe that subTAD reprogramming drives changes in gene expression that promote specific oncogenic pathways and predicts sensitivity to targeted therapy.
The contribution of deregulated chromatin architecture, including topologically associated domains (TADs), to cancer progression remains ambiguous. CCCTC-binding factor (CTCF) is a central regulator of higher-order chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains unclear. We find that under physiological conditions, CTCF organizes subTADs to limit the expression of oncogenic pathways, including phosphatidylinositol 3-kinase (PI3K) and cell adhesion networks. Loss of a single CTCF allele potentiates cell invasion through compromised chromatin insulation and a reorganization of chromatin architecture and histone programming that facilitates de novo promoter-enhancer contacts. However, this change in the higher-order chromatin landscape leads to a vulnerability to inhibitors of mTOR. These data support a model whereby subTAD reorganization drives both modification of histones at de novo enhancer-promoter contacts and transcriptional up-regulation of oncogenic transcriptional networks.
