On Oct. 27th, 2021, Prof. Yi Qin Gao’s group from the College of Chemistry and Molecular Engineering, Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG) in Peking University published a research paper entitled “Computational characterization of domain-segregated 3D chromatin structure and segmented DNA methylation status in carcinogenesis” in Molecular Oncology. The study reveals a general sequence dependence of various genomic and epigenetic changes in carcinogenesis and provides new insights into a more general mechanism of cancer development.

　　Together with DNA methylation and other epigenetic marks, the high-order chromatin structure plays a vital role in gene regulation and displays abnormal status in cancer cells. Theoretical analyses are expected to provide a more unified understanding of the multi-omics data on the large variety of samples and hopefully a common picture of carcinogenesis. In particular, the researchers are interested in whether an underlying origin DNA sequence exists for these epigenetic alterations.

　　Based on the hierarchical distribution of CGIs, the whole genome was divided into two types of megabase-sized domains, CGI-rich domains (named as CGI forest domains) and CGI-poor domains (named as CGI prairie domains). These two types of domains, differing in sequence features, show distinct epigenetic and transcriptional patterns. Furthermore, the cell-specific spatial contact and separation between these two types of domains are strongly coupled with various biological processes, such as early embryonic development, cell differentiation, and senescence.

　　The researchers performed an integrated analysis of DNA methylation, 3D chromatin structure, DNase hypersensitivity, and gene expression in the present study. They found several common trends associated with carcinogenesis in various cancer types: (1) A consistent global chromatin structure change in which the short genomic distance contacts increase at the expense of long-distance contacts, especially at the Mb scale. (2) Enhanced separation of genome segments of different CpG densities at the scales of both CGI (kb) and CGI forests/prairies (Mb). Domains of similar CpG density and methylation level tend to gain contacts. (3) The loss of the contacts of low CpG prairie domains with the CpG rich domains coincides with their hypomethylation and gives rise to a more considerable difference between the open seas in the forest and prairie domains, which is aggravated as the cancer stage increases. (4) The expression level difference between the more active CGI/forests and less active nonCGI/prairies is enlarged in cancer cells, compared to standard samples. These observations suggest that chromatin goes through concerted structure, epigenetics, and expression activity changes that are strongly influenced by sequential properties in cancer development.

　　Concerted changes of DNA methylation, chromatin structure, and gene expression in carcinogenesis.

　　Ph.D. candidate Yue Xue is the paper’s first author, and Prof. Yi Qin Gao is the corresponding author. The work was also contributed by Dr. Ying Yang, Hao Tian, Hui Quan, Sirui Liu, Ling Zhang from Prof. Yi Qin Gao’s lab and Dr. Lu Yang, Haichuan Zhu from Prof. Hong Wu’s lab from School of Life Sciences, Peking-Tsinghua Center for Life Sciences in Peking University and National Clinical Research Center for Hematologic Disease in Peking University People’s Hospital. The project was funded by the National Natural Science Foundation of China.

　　Link: https://doi.org/10.1002/1878-0261.13127