Computational characterization of domain‐segregated 3D chromatin structure and segmented DNA methylation status in carcinogenesis

Abstract

The high‐order chromatin structure, together with DNA methylation and other epigenetic marks, 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, we are interested in the question of whether an underlying origin DNA sequence exists for these epigenetic alterations. The human genome consists of two types of megabase‐sized domain based on the distribution of CpG islands (CGIs) that show distinct structural, epigenetic, and transcriptional properties: CGI‐rich and CGI‐poor domains. Through an integrated analysis of chromatin structure, DNA methylation, and RNA sequencing data, we found that, in carcinogenesis, the two different types of domain display different structural changes and have an increased number of DNA methylation differences and transcriptional‐level differences, compared with in noncancer cells. We also compared the structural features among carcinogenesis, senescence, and mitosis, showing the possible connection between chromatin structure and cell state, which could affect vital cancer‐related properties. In summary, chromatin structure, DNA methylation, and gene expression, as well as their changes observed in several types of cancers, show a dependence on multiscale DNA sequence heterogeneity.

Expression regulation of genes is linked to their CpG density distributions around transcription start sites

“…By comparison, cluster 3 genes display a broad distribution of expression fold change (Fig 4A), suggesting that some genes are dramatically activated/repressed in tumorigenesis (besides, we also performed the shrinkage of logFC and the results remain the same [Fig S9C ]). In addition, consistent with our previous findings (Xue et al, 2022), genes specifically and highly expressed in paracancerous tissue (mainly in cluster 3) are mostly down-regulated in cancer cells (Fig S10A), whereas complementary genes (i.e., genes specifically expressed in other tissues other than paracancerous) are mostly up-regulated (Fig S10B).…”

“…For instance, SLC16A1 and BSG, belonging to cluster 1 and playing vital roles in energy metabolism (Halestrap & Price, 1999;Felmlee et al, 2020), are up-regulated in a variety of cancer types (Fig S9B ) and could promote tumor growth and aggressiveness through the Warburg effect (Vaupel & Multhoff, 2021). This result is consistent with our previous finding that genes with high CpG densities tend to be up-regulated in cancer cells (Xue et al, 2022), indicating that the expression change in carcinogenesis is partially coupled with the CpG density. Nevertheless, Fig 4A shows that although cluster 1 genes are more likely to be up-regulated, the changes tend to be small.…”

Pseudogenes and Liquid Phase Separation in Epigenetic Expression

“…To efficiently package the genome, the chromatin is settled in three dimensional (3D) structure in the nuclear loci. The study shows that the variation in 3D chromatin structure promotes tumorigenesis (29). Furthermore, the evidence points out the impact of LLPS on the 3D structure, where the suppression of liquid phase separate by 1,6-hexanediol compromises the 3D structure organization in living cells (30)(31)(32)(33).…”

Characterization of network hierarchy reflects cell-state specificity in genome organization

“…The recently developed Hi-C technology allows detailed inspection of aberrant chromatin structure in pathological tissues. Radial reorganization of compartment A/B in nucleus was observed in CRC 32 and attenuation of long-range chromatin interactions in Hi-C was seen in multiple cancer cell-lines compared to normal cells 33 . Pathological cancer tissues were observed to be accompanied by disturbances in compartments and TAD structures 32,34,35 .…”

“…In lineage specifications, establishment of long-range promoter-enhancer contacts are correlated with corresponding gene activation 45 . Significant structural changes in chromatin in cancer and cell development underline the importance of genome architecture for maintaining stable cell identities 33,[46][47][48] .…”