Overlapping DNA methylation dynamics in mouse intestinal cell differentiation and early stages of malignant progression
Forn Bernaus, Marta (Institut Germans Trias i Pujol. Institut de Medicina Predictiva i Personalitzada del Càncer)
Díez-Villanueva, Anna (Institut Germans Trias i Pujol. Institut de Medicina Predictiva i Personalitzada del Càncer)
Merlos-Suárez, Anna (Institute for Research in Biomedicine (IRB Barcelona))
Muñoz, Mar (Institut Germans Trias i Pujol. Institut de Medicina Predictiva i Personalitzada del Càncer)
Lois, Sergio (Institut Germans Trias i Pujol. Institut de Medicina Predictiva i Personalitzada del Càncer)
Carrió Gaspar, Elvira (Institut Germans Trias i Pujol. Institut de Medicina Predictiva i Personalitzada del Càncer)
Jordà, Mireia (Institut Germans Trias i Pujol. Institut de Medicina Predictiva i Personalitzada del Càncer)
Bigas Salvans, Anna (Institut Hospital del Mar d'Investigacions Mèdiques)
Batlle, Eduard (Institute for Research in Biomedicine (IRB Barcelona))
Peinado Morales, Miguel Á. (Miguel Ángel) (Institut Germans Trias i Pujol. Institut de Medicina Predictiva i Personalitzada del Càncer)

Date:	2015
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.
Grants:	Ministerio de Economía y Competitividad PTC2011-1091 Ministerio de Economía y Competitividad SAF2011/23638
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	DNA methylation ; Cell differentiation ; Mammalian genomics ; Gastrointestinal tract ; Adenomas ; Gene expression ; Colon ; Epigenetics
Published in:	PloS one, Vol. 10, No. 5 (May 2015) , p. e0123263, ISSN 1932-6203

DOI: 10.1371/journal.pone.0123263
PMID: 25933092

22 p, 1.4 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles