Abstract
Mouse models of intestinal crypt cell differentiation and tumorigenesis have been used to characterize the molecular mechanisms underlying both processes. DNA methylation is a key epigenetic mark and plays an important role in cell identity and differentiation programs and cancer. To get insights into the dynamics of cell differentiation and malignant transformation we have compared the DNA methylation profiles along the mouse small intestine crypt and early stages of tumorigenesis. Genome-scale analysis of DNA methylation together with microarray gene expression have been applied to compare intestinal crypt stem cells (EphB2high), differentiated cells (EphB2negative), ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Compared with late stages, small intestine crypt differentiation and early stages of tumorigenesis display few and relatively small changes in DNA methylation. Hypermethylated loci are largely shared by the two processes and affect the proximities of promoter and enhancer regions, with enrichment in genes associated with the intestinal stem cell signature and the PRC2 complex. The hypermethylation is progressive, with minute levels in differentiated cells, as compared with intestinal stem cells, and reaching full methylation in advanced stages. Hypomethylation shows different signatures in differentiation and cancer and is already present in the non-tumor tissue adjacent to the adenomas in ApcMin/+ mice, but at lower levels than advanced cancers. This study provides a reference framework to decipher the mechanisms driving mouse intestinal tumorigenesis and also the human counterpart.
Highlights
The intestine is a fascinating organ exposed to very dynamic environmental factors including food, toxins and a complex microbiota
Our analysis indicates that intestinal cell differentiation is accompanied by small changes in DNA methylation, mostly consisting in hypermethylations that affect less than 2% of the genome analyzed by AIMS-Seq
Our analysis shows that DNA methylation changes along small intestine crypt differentiation and early stages of tumorigenesis are few and small compared with late stages
Summary
The intestine is a fascinating organ exposed to very dynamic environmental factors including food, toxins and a complex microbiota. Deregulation of cell proliferation and differentiation processes may lead to malignant transformation and propagation of intestinal cancer stem cells [2]. The intestinal epithelial layer has a turnover of 5 days and is folded forming the crypts [3]. The cellular differentiation occurs along the crypt axis and the terminally differentiated cells of the small intestine migrate towards the tips of villi (protrusions into the small intestine lumen). Important methodological advances have been made in crypt’s cells isolation and propagation [3,5,6] allowing the characterization of the expression signatures of the different cellular fractions [2,7,8,9,10,11,12,13,14]
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