Early-stage formation of an epigenetic field defect in a mouse colitis model, and non-essential roles of T- and B-cells in DNA methylation induction

Abstract

Epigenetic fields for cancerization are involved in development of human cancers, especially those associated with inflammation and multiple occurrences. However, it is still unclear when such field defects are formed and what component of inflammation is involved in induction of aberrant DNA methylation. Here, in a mouse colitis model induced by dextran sulfate sodium (DSS), we identified three CpG islands specifically methylated in colonic epithelial cells exposed to colitis. Their methylation levels started to increase as early as 8 weeks after DSS treatment and continued to increase until colon cancers developed at 15 weeks. In contrast to the temporal profile of DNA methylation levels, infiltration of inflammatory cells spiked immediately after the DSS treatment and then gradually decreased. Exposure of cultured colonic epithelial cells to DSS did not induce DNA methylation and it was indicated that inflammation triggered by the DSS treatment was responsible for methylation induction. To clarify components of inflammation involved, severe combined immunodeficiency (SCID) mice that lack functional T-and B-cells were similarly treated. Even in SCID mice, DNA methylation, along with colon tumors, were induced at the same levels as in their background strain of mice (C.B17). Comparative analysis of inflammation-related genes showed that Ifng, Il1b and Nos2 had expression concordant with methylation induction whereas Il2, Il6, Il10, Tnf did not. These results showed that an epigenetic field defect is formed at early stages of colitis-associated carcinogenesis and that functional T and B cells are non-essential for the formation.

Molecular Pathways: Involvement of Helicobacter pylori–Triggered Inflammation in the Formation of an Epigenetic Field Defect, and Its Usefulness as Cancer Risk and Exposure Markers

“…Increased production of NO in vitro is reported to increase the enzyme activity of DNA methyltransferases without changing their expression, and to induce DNA methylation of specific genes (52). In the human and gerbil stomachs infected by H. pylori and mouse colons treated with DSS, no changes in the expression of DNA methyltransferases 1, 3a, and 3b were observed (28,45,49). It is possible that a signal from chronic inflammation, possibly IL1b, and elevation of NO in epithelial cells lead to inappropriate localization of deregulated DNA methyltransferase(s) to methylation-susceptible CpG islands (see below) and induce aberrant DNA methylation as an infrequent event.…”

Epigenetic field defects in progression to cancer

“…We read with great interest the recent article by Katsurano et al [1] describing a mouse colitis model leading to tumor formation. They report that an epigenetic field defect forms early after treatment with dextran sulfate sodium (DSS) and that the epigenetic alterations continue to increase even with diminishing stimulation.…”

“…In addition to epigenetic alteration of expression of miRNAs, other common types of epigenetic alterations in cancers that change gene expression levels include direct hypermethylation or hypomethlyation of CpG islands of protein-encoding genes and alterations in histones and chromosomal architecture that influence gene expression [10,11] . The specific epigenetic alterations studied by Katsurano et al [1] , as well as epigenetic field defects in general, can be placed in a broad explanatory framework starting with the occurrence of DNA damage, a major primary event in progression to cancer as shown in Figure 1. In Figure 1 italicized capitalized abbreviations are symbols of epigenetically altered genes.…”

“…ERCC1, WRN, MSH2, PMS2, MLH1 and MGMT are symbols for specific DNA repair genes. FOSb, FUT4, HOXa5, MEX3a, MSX1, SOX11 are symbols for epigenetically altered genes described by Katsurano et al [1] . These symbols for the genes (in the …”

Chronic Inflammation Induces a Novel Epigenetic Program That Is Conserved in Intestinal Adenomas and in Colorectal Cancer

“…While a few initial studies have suggested aberrant methylation patterns in mouse models of IBD (14,15), both the effect of inflammation on DNA methylation and the functional outcome have not been investigated in detail yet. We have now used whole-genome bisulfite sequencing (16) to characterize the methylomes of the AOM/DSS mouse model at single-base resolution.…”