Metz Reed Kathleen S, Fritz Andrew, Greenyer Haley, Heselmeyer-Haddad Kerstin, Frietze Seth, Stein Janet, Stein Gary, Misteli Tom
National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Biochemistry and University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT, USA.
bioRxiv. 2025 May 17:2025.05.14.654144. doi: 10.1101/2025.05.14.654144.
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.
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 differentially expressed genes physically connected to distal regulatory elements. While changes in chromatin loops were relatively rare during progression, differential loops were enriched for progression-associated genes, including those involved in proliferation, angiogenesis, and differentiation. Changes in either enhancer-promoter contacts or distal enhancer activity were accompanied by differential gene regulation, suggesting that changes in chromatin contacts are not necessary but can be suYicient for gene regulation.
Together, our results demonstrate a functionally relevant connection between gene regulation and genome remodeling at many key genes during cancer progression.
癌细胞在表观遗传模式上经历广泛变化，这些变化在癌症进展过程中介导了癌症相关基因表达程序的改变。然而，这些变化发生的高阶基因组组织的改变及其功能影响尚不太清楚。为了在精细尺度和全基因组范围内探索癌症进展过程中染色质结构和基因组结构的表观遗传参数如何变化，我们在非恶性、癌前和转移性MCF10乳腺癌上皮细胞中生成了高分辨率的Micro-C接触图谱。
我们分析了染色质区室、拓扑相关结构域（TADs）和染色质环的进展相关重组，并确定了不变的染色质特征。我们发现大规模的区室转移主要发生在癌症发展的早期阶段，在向转移的后期转变过程中，TADs和环化的更精细结构变化不断积累。我们将这些结构特征与基因表达、组蛋白标记和潜在增强子的变化联系起来，发现很大一部分差异表达基因与远端调控元件存在物理连接。虽然染色质环的变化在进展过程中相对较少，但差异环富含与进展相关的基因，包括那些参与增殖、血管生成和分化的基因。增强子-启动子接触或远端增强子活性的变化伴随着差异基因调控，这表明染色质接触的变化不是必需的，但足以进行基因调控。
总之，我们的结果证明了癌症进展过程中许多关键基因的基因调控与基因组重塑之间存在功能上的相关联系。
