Genome reorganization and its functional impact during breast cancer progression
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Background
Cancer cells undergo widespread changes in epigenetic patterns that mediate cancer compromised gene expression programs during cancer progression. However, the alterations in higher-order genome organization in which these changes occur and their functional implications are less well understood. To explore how chromatin structure and epigenetic parameters of genome architecture changes during cancer progression at a fine scale and genome-wide, we generated high-resolution Micro-C contact maps in non-malignant, pre-cancerous, and metastatic MCF10 breast cancer epithelial cells.
Results
We profiled progression-associated reorganization of chromatin compartments, topologically associated domains (TADs), and chromatin loops, and also identified invariable chromatin features. We find large-scale compartmental shifts occur predominantly in early stages of cancer development, with more fine-scale structural changes in TADs and looping accumulating during the later transition to metastasis. We related these structural features to changes in gene expression, histone marks, and potential enhancers and found a large portion of diYerentially expressed genes physically connected to distal regulatory elements. While changes in chromatin loops were relatively rare during progression, diYerential loops were enriched for progression-associated genes, including those involved in proliferation, angiogenesis, and diYerentiation. Changes in either enhancer-promoter contacts or distal enhancer activity were accompanied by diYerential gene regulation, suggesting that changes in chromatin contacts are not necessary but can be suYicient for gene regulation.
Conclusions
Together, our results demonstrate a functionally relevant connection between gene regulation and genome remodeling at many key genes during cancer progression.
KEY FINDINGS
‒ The cancer genome is reorganized throughout cancer progression at the level of compartments, chromatin domains, and loops
‒ Compartmental shifts occur in early stages of cancer development, with more fine-scale structural changes accumulating during metastasis
‒ Chromatin domain boundaries are weakened during cancer progression
‒ Many progression-regulated genes exhibit changes in distal enhancer histone modifications that are bridged by stable chromatin loops
‒ Changes in enhancer activity or subtle changes in chromatin contacts can rewire enhancer-promoter connections to facilitate changes in gene expression
‒ Prominent changes in chromatin loops occur at a small subset of diYerentially regulated genes during progression
