Domain segregated 3D chromatin structure and segmented DNA methylation in carcinogenesis

Abstract

The three-dimensional (3D) chromatin structure, together with DNA methylation and other epigenetic marks, profoundly affects gene expression and displays abnormal behaviors in cancer cells. We elucidated the chromatin architecture remodeling in carcinogenesis from the perspective of spatial interactions between CGI forest and prairie domains, which are two types of megabase-sized domains defined by different sequence features but show distinct epigenetic and transcriptional patterns. DNA sequence strongly affects chromosome spatial interaction, DNA methylation and gene expression. Globally, forests and prairies show enhanced spatial segregation in cancer cells and such structural changes are accordant with the alteration of CGI interactions and domain boundary insulation, which could affect vital cancer-related properties. As the cancer progresses, a gradual increase of the DNA methylation difference between the two types of DNA domains is also observed for many different types of cancers. These observations are consistent with the change of transcriptional level differences of genes in these two domains, suggesting a highly-connected global structural, epigenetic and transcriptional activity changes in carcinogenesis.3 development and its relationship with chromosomal structural changes remain largely unknown.In principle, both chromosomal structure and epigenetic modifications can influence gene expression. Based on Hi-C contact map, the chromatin is divided into compartments A and B (2).Genes are enriched in compartment A and their expression levels are higher than those in compartment B. But there are many questions remain unanswered, e.g. what factors determine the compartment formation, what are the driving forces of compartment switch, and what are the roles of compartmentalization in cancer? Our previous study (25) showed that the compartment formation is strongly related to the genome composition. Based on the uneven 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 and overlap strongly with the compartments A and B, respectively. 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 (26), cell differentiation, and senescence (27). The main goal of this study is to understand the sequence dependence of various carcinogenesis marks and we found that forest and prairie behave significantly differently, including their distribution in compartments, CGI interactions, TAD formation, gene expression and epigenetic marks, especially DNA methylation, which is closely associated with development stage of cancer. The property difference between forest and prairie enlarges in cancer, consistent with their increased spatial separati...

Progressive Domain Segregation in Early Embryonic Development and Underlying Correlation to Genetic and Epigenetic Changes

“…Xuan Ming et al also found that solo-WCGW sites display aging-and cancer-associated hypomethylation, which exhibits low maintenance efficiency during the cell cycle [37]. For chromatin structural changes, we compared the segregation ratio in the G1 stage to that in the late S~G2 stage, and found that forests and prairies tend to become more separated in the late S~G2 stage [35]. The enhanced segregation supports the hypothesis that mitosis is conducive to a more segregated chromatin structure.…”

“…Earlier studies have found that DNA hypomethylation, which is more likely to occur in prairie domains, correlates with the cell cycles. Partially methylated domains (PMDs) in tumor cells are mainly composed of prairies [35], and PMD hypomethylation increases with age, which appears to track the accumulation of cell divisions [36]. Xuan Ming et al also found that solo-WCGW sites display aging-and cancer-associated hypomethylation, which exhibits low maintenance efficiency during the cell cycle [37].…”

Progressive domain segregation in early embryonic development and underlying correlation to genetic and epigenetic changes

“…Xuan Ming et al also found that solo-WCGW sites display aging- and cancer-associated hypomethylation, which exhibit low maintenance efficiency during cell cycle(Ming et al, 2020). For chromatin structural changes, we compared the segregation ratio in G1 stage to that in the late S ~ G2 stage, and found that forest and prairie tend to become more separated in the late S ~ G2 stage (the related figure can be found in Xue et al, 2020). The enhanced segregation supports that mitosis is conducive to a more segregated chromatin structure.…”

“…Earlier studies have found that DNA hypomethylation, which is more likely to occur in prairie domains, correlates with the cell cycles. Partially methylated domains (PMDs) in tumor cells are mainly composed of prairies (Xue et al, 2020) and PMD hypomethylation increases with age, which appears to track the accumulation of cell divisions (Zhou et al, 2018). Xuan Ming et al also found that solo-WCGW sites display aging-and cancerassociated hypomethylation, which exhibit low maintenance efficiency during cell cycle (Ming et al, 2020).…”

Progressive domain segregation in early embryonic development and underlying correlation to genetic and epigenetic changes

“…Xuan Ming et al also found that solo-WCGW sites display aging- and cancer-associated hypomethylation, which exhibit low maintenance efficiency during cell cycle(Ming et al, 2020). For chromatin structural changes, we compared the segregation ratio in G1 stage to that in the late S ~ G2 stage, and found that forest and prairie tend to become more separated in the late S ~ G2 stage (Xue et al, 2020). The enhanced segregation supports that mitosis is conducive to a more segregated chromatin structure.…”