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.