Researchers characterize the 3D chromatin structure and segmented DNA methylation to understand its role in carcinogenesis

DNA methylation is an important regulator of gene transcription, and its role in carcinogenesis has been a topic of considerable interest in the last few years. Alterations in DNA methylation are common in a variety of tumors as well as in development. Many of these epigenetic changes occur early in tumorigenesis and are highly pervasive across a tumor type. Therefore, DNA methylation is highly suitable as a biomarker for early cancer detection and its tumor-type specificity can be exploited in many areas of research development such as cancer treatment. These abnormal changes in DNA structure can be visualized in the cancer cells using modern technology and sequencing-based methods like (3C) technology and its derived methods, such as Hi-C. Though there is no doubt that visible changes are present in cancer, these changes are ill-defined. Defining these changes will be important for understanding various cancers. In a new study published in Journal of Molecular Oncology, Yue Xue, Ying Yang, Hao Tian, Hui Quan, Sirui Liu, Ling Zhang, Lu Yang, Haichuan Zhu, and Hong Wu, led by Professor Yi Qin Gao from Peking University, sought to identify these changes. This study used the whole-genome bisulfite sequencing (WGBS) data of methylomes obtained from The Cancer Genome Atlas (TCGA) project and Gene Expression Omnibus, which includes 48 cancer samples and 17 matched adjacent samples, as well as paired cancer and normal data of 4 liver, 3 lung, and 2 colon cancer samples. Xue et al. utilized computational modeling to define higher-level changes in the chromatin structure that are distinct in tumors cells compared to normal cells. Specifically, these distinctions are based on the altered distribution of megabase-sized domains of CpG-island (CGI)-rich and CGI-poor regions and can distinguish multiple cancer types from non-cancer cells.

Using their computational model, the research team identified numerous trends associated with different cancer types. They found consistent chromatin structure changes in cancer cells, such as short genomic distance contacts increased at the expense of long-distance contacts. They also visualized enhanced separation of genome segments of different CpG densities, with increased contact between domains with similar CpG densities and methylation levels. The authors further report that these changes in chromatin structure result in hypomethylation in carcinogenesis that is exacerbated with cancer stage, and that there are greater differences in expression levels of genes within active CGI/forests compared to less active non-CGI/prairies in cancer cells than normal cells. These findings confirm that, in cancer development, chromatin goes through specific and concerted structural and epigenetic changes to result in changes in gene expression.

In a nutshell, the authors showed that different types of cancers exhibit significant and consistent structural, epigenetic, and gene expression changes especially in CGI and CGI forest/prairies. Although it is too early to define the role of these changes in the development of specific cancer, this new study confirmed that such changes can be utilized as markers for different cancer types and may be important players in cancer development. Further research in this area will be aimed at clarifying a causal relationship between the structure, epigenetics, and expression levels, as well as understanding the significance of the different changes among cancer types.

In a statement to Medicine Innovates series, Professor Yi Qin Gao, the lead and corresponding author said, “This is a novel way to better understand the development of cancer, visualizing carcinogenesis, and differentiating cancer types for better treatment options. While the technology can still be refined with more datasets, this could become an important tool for cancer diagnostics and finding new treatment methods.”