DNA–Methylome Analysis of Mouse Intestinal Adenoma Identifies a Tumour-Specific Signature That Is Partly Conserved in Human Colon Cancer
et al. (2013) DNA-Methylome Analysis of Mouse Intestinal Adenoma Identifies a Tumour-Specific
Signature That Is Partly Conserved in Human Colon Cancer. PLoS Genet 9(2): e1003250. doi:10.1371/journal.pgen.1003250
DNA-Methylome Analysis of Mouse Intestinal Adenoma Identifies a Tumour-Specific Signature That Is Partly Conserved in Human Colon Cancer
Christina Grimm 0
Lukas Chavez 0
Mireia Vilardell 0
Alexandra L. Farrall 0
Sascha Tierling 0
Julia W. Bo hm 0
Phillip Grote 0
Matthias Lienhard 0
Jo rn Dietrich 0
Bernd Timmermann 0
Jo rn Walter 0
Michal R. Schweiger 0
Hans Lehrach 0
Ralf Herwig 0
Bernhard G. Herrmann 0
Markus Morkel 0
Dirk Schu beler, Friedrich Miescher Institute for Biomedical Research, Switzerland
0 1 Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics , Berlin, Germany , 2 Charite Universita tsmedizin Berlin, Department of Rheumatology , Berlin, Germany , 3 Max Planck Institute for Molecular Genetics, Department of Developmental Genetics , Berlin, Germany, 4 Universita t des Saarlandes, FR 8.3 Biowissenschaften, Genetik/Epigenetik Campus, Saarbru cken, Germany , 5 Max Planck Institute for Molecular Genetics, Next Generation Sequencing Core Facility , Berlin, Germany , 6 Charite Universita tsmedizin Berlin, Institute for Medical Genetics , Berlin, Germany, 7 Charite Universita tsmedizin Berlin , Laboratory of Molecular Tumor Pathology , Berlin , Germany
Aberrant CpG methylation is a universal epigenetic trait of cancer cell genomes. However, human cancer samples or cell lines preclude the investigation of epigenetic changes occurring early during tumour development. Here, we have used MeDIP-seq to analyse the DNA methylome of APCMin adenoma as a model for intestinal cancer initiation, and we present a list of more than 13,000 recurring differentially methylated regions (DMRs) characterizing intestinal adenoma of the mouse. We show that Polycomb Repressive Complex (PRC) targets are strongly enriched among hypermethylated DMRs, and several PRC2 components and DNA methyltransferases were up-regulated in adenoma. We further demonstrate by bisulfite pyrosequencing of purified cell populations that the DMR signature arises de novo in adenoma cells rather than by expansion of a pre-existing pattern in intestinal stem cells or undifferentiated crypt cells. We found that epigenetic silencing of tumour suppressors, which occurs frequently in colon cancer, was rare in adenoma. Quite strikingly, we identified a core set of DMRs, which is conserved between mouse adenoma and human colon cancer, thus possibly revealing a global panel of epigenetically modified genes for intestinal tumours. Our data allow a distinction between early conserved epigenetic alterations occurring in intestinal adenoma and late stochastic events promoting colon cancer progression, and may facilitate the selection of more specific clinical epigenetic biomarkers.
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Funding: The study was funded in part by NGFNplus grants to JW, MRS, HL, RH, BGH, and MM (PKT-01GS08111). ALF was funded by a Max Planck Postdoctoral
Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Epigenetic mechanisms play critical roles in controlling the
cellular transcript repertoire and ultimately cellular phenotypes.
The methylation of cytosine bases of CpG dinucleotides, as well as
the covalent modification of histone proteins represent major
target sites of the protein complexes involved in epigenetic control.
Epigenetic histone and DNA codes are established and interpreted
in a combinatorial fashion, and both interact in the short-term
regulation of gene activity and in the establishment of long-term
epigenetic memory, such as heterochromatin formation and gene
silencing [1,2]. The Polycomb Repressive Complexes (PRC1 and
PRC2) and Trithorax Group Complexes (TrxG) are major histone
modifying protein complexes setting repressive or activating
marks, respectively, while CpG methylation patterns are set and
propagated by DNA methlytransferases (DNMTs). A major role of
the PRC2 complex in development is to tag gene regulatory
sequences with a specific tri-methyl mark on lysine 27 of histone 3
(H3K27me3), resulting in short-term transcriptional repression
[3]. Moreover, PRC2 complexes can also interact with DNMTs,
and initiate long-term silencing of genes via de-novo CpG
methylation [4]. By default, non-transformed cells are
characterized by high genome-wide CpG methylation, with the exception of
CpG islands (CGIs), which are mostly unmethylated [1,2,5].
Tumour cells contain aberrant epigenomes [4,612]. Tumours
are characterized by general genomic hypomethylation of CpGs,
while CGIs are hypermethylated [13]. It has been found that
histone modification patterns of tumour cells resemble those found
in embryonic stem cells and likely guide CpG methylation [ (...truncated)