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Changes in correlation between promoter methylation and gene expression in cancer.

Moarii M, Boeva V, Vert JP, Reyal F - BMC Genomics (2015)

Bottom Line: Methylation of high-density CpG regions known as CpG Islands (CGIs) has been widely described as a mechanism associated with gene expression regulation.However, this hypermethylation is not accompanied by a decrease in expression of the corresponding genes, which are already lowly expressed in the normal genes.It may instead modify how the expression of a few specific genes, particularly transcription factors, are associated with DNA methylation variations in a tissue-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: CBIO-Centre for Computational Biology, Mines Paristech, PSL-Research University, 35 Rue Saint-Honore, Fontainebleau, F-77300, France. matahi.moarii@mines-paristech.fr.

ABSTRACT

Background: Methylation of high-density CpG regions known as CpG Islands (CGIs) has been widely described as a mechanism associated with gene expression regulation. Aberrant promoter methylation is considered a hallmark of cancer involved in silencing of tumor suppressor genes and activation of oncogenes. However, recent studies have also challenged the simple model of gene expression control by promoter methylation in cancer, and the precise mechanism of and role played by changes in DNA methylation in carcinogenesis remains elusive.

Results: Using a large dataset of 672 matched cancerous and healthy methylomes, gene expression, and copy number profiles accross 3 types of tissues from The Cancer Genome Atlas (TCGA), we perform a detailed meta-analysis to clarify the interplay between promoter methylation and gene expression in normal and cancer samples. On the one hand, we recover the existence of a CpG island methylator phenotype (CIMP) with prognostic value in a subset of breast, colon and lung cancer samples, where a common subset of promoter CGIs hypomethylated in normal samples become hypermethylated. However, this hypermethylation is not accompanied by a decrease in expression of the corresponding genes, which are already lowly expressed in the normal genes. On the other hand, we identify tissue-specific sets of genes, different between normal and cancer samples, whose inter-individual variation in expression is significantly correlated with the variation in methylation of the 3' flanking regions of the promoter CGIs. These subsets of genes are not the same in the different tissues, nor between normal and cancerous samples, but transcription factors are over-represented in all subsets.

Conclusion: Our results suggest that epigenetic reprogramming in cancer does not contribute to cancer development via direct inhibition of gene expression through promoter hypermethylation. It may instead modify how the expression of a few specific genes, particularly transcription factors, are associated with DNA methylation variations in a tissue-dependent manner.

No MeSH data available.


Related in: MedlinePlus

Shift of epigenetic regulation in cancer. Scatterplot between the predictive power of DNA methylation for gene expression in normal and cancerous breast tissues shows little correlation (R2=0.04)
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Fig8: Shift of epigenetic regulation in cancer. Scatterplot between the predictive power of DNA methylation for gene expression in normal and cancerous breast tissues shows little correlation (R2=0.04)

Mentions: Results in the previous section suggest that for a subset of genes, a significant correlation between promoter methylation and gene expression is observed, which may be due for example to a direct regulation of gene expression by promoter methylation. To assess whether this correlation is conserved across tissues, we compare the predictive powers of methylation for each gene when it is computed on normal or cancerous samples from different tissues. As shown on Additional file 14, however, we observe little correlation between the predictive power across tissues in normal and in cancer samples, suggesting that the association between promoter methylation and gene expression is tissue-specific (, , , ). We also observe very little correlation between predictive powers in normal and cancerous tissues, which could suggests a shift of the epigenetic regulation mechanism during cancer development (Fig. 8, Additional file 15, , ).Fig. 8


Changes in correlation between promoter methylation and gene expression in cancer.

Moarii M, Boeva V, Vert JP, Reyal F - BMC Genomics (2015)

Shift of epigenetic regulation in cancer. Scatterplot between the predictive power of DNA methylation for gene expression in normal and cancerous breast tissues shows little correlation (R2=0.04)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4625954&req=5

Fig8: Shift of epigenetic regulation in cancer. Scatterplot between the predictive power of DNA methylation for gene expression in normal and cancerous breast tissues shows little correlation (R2=0.04)
Mentions: Results in the previous section suggest that for a subset of genes, a significant correlation between promoter methylation and gene expression is observed, which may be due for example to a direct regulation of gene expression by promoter methylation. To assess whether this correlation is conserved across tissues, we compare the predictive powers of methylation for each gene when it is computed on normal or cancerous samples from different tissues. As shown on Additional file 14, however, we observe little correlation between the predictive power across tissues in normal and in cancer samples, suggesting that the association between promoter methylation and gene expression is tissue-specific (, , , ). We also observe very little correlation between predictive powers in normal and cancerous tissues, which could suggests a shift of the epigenetic regulation mechanism during cancer development (Fig. 8, Additional file 15, , ).Fig. 8

Bottom Line: Methylation of high-density CpG regions known as CpG Islands (CGIs) has been widely described as a mechanism associated with gene expression regulation.However, this hypermethylation is not accompanied by a decrease in expression of the corresponding genes, which are already lowly expressed in the normal genes.It may instead modify how the expression of a few specific genes, particularly transcription factors, are associated with DNA methylation variations in a tissue-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: CBIO-Centre for Computational Biology, Mines Paristech, PSL-Research University, 35 Rue Saint-Honore, Fontainebleau, F-77300, France. matahi.moarii@mines-paristech.fr.

ABSTRACT

Background: Methylation of high-density CpG regions known as CpG Islands (CGIs) has been widely described as a mechanism associated with gene expression regulation. Aberrant promoter methylation is considered a hallmark of cancer involved in silencing of tumor suppressor genes and activation of oncogenes. However, recent studies have also challenged the simple model of gene expression control by promoter methylation in cancer, and the precise mechanism of and role played by changes in DNA methylation in carcinogenesis remains elusive.

Results: Using a large dataset of 672 matched cancerous and healthy methylomes, gene expression, and copy number profiles accross 3 types of tissues from The Cancer Genome Atlas (TCGA), we perform a detailed meta-analysis to clarify the interplay between promoter methylation and gene expression in normal and cancer samples. On the one hand, we recover the existence of a CpG island methylator phenotype (CIMP) with prognostic value in a subset of breast, colon and lung cancer samples, where a common subset of promoter CGIs hypomethylated in normal samples become hypermethylated. However, this hypermethylation is not accompanied by a decrease in expression of the corresponding genes, which are already lowly expressed in the normal genes. On the other hand, we identify tissue-specific sets of genes, different between normal and cancer samples, whose inter-individual variation in expression is significantly correlated with the variation in methylation of the 3' flanking regions of the promoter CGIs. These subsets of genes are not the same in the different tissues, nor between normal and cancerous samples, but transcription factors are over-represented in all subsets.

Conclusion: Our results suggest that epigenetic reprogramming in cancer does not contribute to cancer development via direct inhibition of gene expression through promoter hypermethylation. It may instead modify how the expression of a few specific genes, particularly transcription factors, are associated with DNA methylation variations in a tissue-dependent manner.

No MeSH data available.


Related in: MedlinePlus