Abstract
BackgroundDespite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field. In order to evaluate their importance in colorectal cancer (CRC), we generated the first genome-wide histone modification profiles in paired normal colon mucosa and tumor samples.MethodsChromatin immunoprecipitation and microarray hybridization (ChIP-chip) was used to identify promoters enriched for histone H3 trimethylated on lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in paired normal colon mucosa and tumor samples from two CRC patients and for the CRC cell line HT29.ResultsBy comparing histone modification patterns in normal mucosa and tumors, we found that alterations predicted to have major functional consequences were quite rare. Furthermore, when normal or tumor tissue samples were compared to HT29, high similarities were observed for H3K4me3. However, the differences found for H3K27me3, which is important in determining cellular identity, indicates that cell lines do not represent optimal tissue models. Finally, using public expression data, we uncovered previously unknown changes in CRC expression patterns. Genes positive for H3K4me3 in normal and/or tumor samples, which are typically already active in normal mucosa, became hyperactivated in tumors, while genes with H3K27me3 in normal and/or tumor samples and which are expressed at low levels in normal mucosa, became hypersilenced in tumors.ConclusionsGenome wide histone modification profiles can be used to find epigenetic aberrations in genes associated with cancer. This strategy gives further insights into the epigenetic contribution to the oncogenic process and may identify new biomarkers.
Highlights
Despite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field
Genome wide histone modification profiles can be used to find epigenetic aberrations in genes associated with cancer
Two of the most relevant histone modifications, both in general and from a cancer perspective, are histone H3 lysine 4 trimethylation (H3K4me3), which is found in promoters of active genes and histone H3 lysine 27 trimethylation (H3K27me3), which is preferentially associated with promoters of inactive genes [6]
Summary
Despite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field. Altered DNA methylation is nowadays considered a hallmark of neoplasia, including two different phenomena in cancer cells: global hypomethylation and CpG-promoter hypermethylation of tumor suppressor genes [1,2]. SMYD3, a histone methyl transferase specific for H3K4, is over expressed in colorectal, hepatic and breast cancers, suggesting that H3K4 hypermethylation can occur at promoters of oncogenes [7]. MLL, another H3K4 methyltransferase, is frequently translocated in various forms of leukaemia [8] and the polycomb protein EZH2, a H3K27 specific histone methyl-transferase, is altered in multiple types of cancer [9]. Recent reports suggest that H3K27me mediated silencing of tumor suppressor genes is a frequent event in prostate cancer [10,11]
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