Unraveling the key role of chromatin structure in cancer development through epigenetic landscape characterization of oral cancer

作者：Yue Xue, Lu Liu, Ye Zhang, Yueying He, Jingyao Wang, Zicheng Ma, Tiejun Li, Jianyun Zhang, Yanyi Huang, Yi Qin Gao · 发表于：Molecular Cancer · 年份：2024 · DOI：10.1186/s12943-024-02100-0 · 被引用次数：21 · 研究领域：Epigenetics and DNA Methylation、Chromatin Remodeling and Cancer、RNA modifications and cancer

Epigenetic alterations, such as those in chromatin structure and DNA methylation, have been extensively studied in a number of tumor types. But oral cancer, particularly oral adenocarcinoma, has received far less attention. Here, we combined laser-capture microdissection and muti-omics mini-bulk sequencing to systematically characterize the epigenetic landscape of oral cancer, including chromatin architecture, DNA methylation, H3K27me3 modification, and gene expression. In carcinogenesis, tumor cells exhibit reorganized chromatin spatial structures, including compromised compartment structures and altered gene-gene interaction networks. Notably, some structural alterations are observed in phenotypically non-malignant paracancerous but not in normal cells. We developed transformer models to identify the cancer propensity of individual genome loci, thereby determining the carcinogenic status of each sample. Insights into cancer epigenetic landscapes provide evidence that chromatin reorganization is an important hallmark of oral cancer progression, which is also linked with genomic alterations and DNA methylation reprogramming. In particular, regions of frequent copy number alternations in cancer cells are associated with strong spatial insulation in both cancer and normal samples. Aberrant methylation reprogramming in oral squamous cell carcinomas is closely related to chromatin structure and H3K27me3 signals, which are further influenced by intrinsic sequence properties. Our f...