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Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer

View Article: PubMed Central - PubMed

ABSTRACT

Bivalent (poised or paused) chromatin comprises activating and repressing histone modifications at the same location. This combination of epigenetic marks at promoter or enhancer regions keeps genes expressed at low levels but poised for rapid activation. Typically, DNA at bivalent promoters is only lowly methylated in normal cells, but frequently shows elevated methylation levels in cancer samples. Here, we developed a universal classifier built from chromatin data that can identify cancer samples solely from hypermethylation of bivalent chromatin. Tested on over 7,000 DNA methylation data sets from several cancer types, it reaches an AUC of 0.92. Although higher levels of DNA methylation are often associated with transcriptional silencing, counter-intuitive positive statistical dependencies between DNA methylation and expression levels have been recently reported for two cancer types. Here, we re-analyze combined expression and DNA methylation data sets, comprising over 5,000 samples, and demonstrate that the conjunction of hypermethylation of bivalent chromatin and up-regulation of the corresponding genes is a general phenomenon in cancer. This up-regulation affects many developmental genes and transcription factors, including dozens of homeobox genes and other genes implicated in cancer. Thus, we reason that the disturbance of bivalent chromatin may be intimately linked to tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

Expression and DNA methylation of cancer cell lines.(A) DNA methylation and expression changes of FBSs in BL cell lines against BL fresh tissues (top left), KARPAS-422 against FL fresh tissues (top right), lymphoma cell lines against normal germinal center B-cells (bottom left) and germinal center B-cells against FL fresh tissues. Changes are shown relative to the cell lines. The number of pairs in each quadrant is shown. (B) Expression change of FBS genes (blue) and other genes against normal cells in glioblastoma fresh tissue (left) and in cancer cell lines after a number of passages. At the right, the value for commonly used cell lines is shown. (C) Relative methylation of classifier FBSs in cancer cell lines, fresh cancer tissue, normal cell lines and normal tissue.
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f6: Expression and DNA methylation of cancer cell lines.(A) DNA methylation and expression changes of FBSs in BL cell lines against BL fresh tissues (top left), KARPAS-422 against FL fresh tissues (top right), lymphoma cell lines against normal germinal center B-cells (bottom left) and germinal center B-cells against FL fresh tissues. Changes are shown relative to the cell lines. The number of pairs in each quadrant is shown. (B) Expression change of FBS genes (blue) and other genes against normal cells in glioblastoma fresh tissue (left) and in cancer cell lines after a number of passages. At the right, the value for commonly used cell lines is shown. (C) Relative methylation of classifier FBSs in cancer cell lines, fresh cancer tissue, normal cell lines and normal tissue.

Mentions: Earlier cell line based studies of hypermethylation in bivalent regions did not report an up-regulation of associated genes15. To investigate this discrepancy, we compared DNA methylation16 and gene expression40414243 of lymphoma cell lines to fresh cancer tissue and normal control cells. Indeed, our comparison revealed a hypermethylation of bivalent regions accompanied by a down-regulation of associated genes in the cell lines when compared to fresh cancer tissues (Fig. 6A). Our re-analysis of expression data of a glioblastoma cell line freshly generated by Lee et al.44 indicated that FBS genes are gradually silenced with each passage. After a couple of passages, FBS genes show an expression profile close to that in control cells and other established cell lines (Fig. 6B). We could confirm the repression of FBS genes in independent data from cervix carcinoma cell lines45 and also found a small but significant (p < 0.008) reduction of FBS gene expression in freshly generated cell lines from lung carcinoma metastasis46 (Supplementary Fig. S10). We also investigated whether the relative classifier CpG methylation of cell lines is different to the one of primary tissues. Cancer cell lines (but not normal cell lines) showed a significantly higher relative descriptor CpG methylation than fresh cancer tissues (p < 10−13, Fig. 6C).


Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer
Expression and DNA methylation of cancer cell lines.(A) DNA methylation and expression changes of FBSs in BL cell lines against BL fresh tissues (top left), KARPAS-422 against FL fresh tissues (top right), lymphoma cell lines against normal germinal center B-cells (bottom left) and germinal center B-cells against FL fresh tissues. Changes are shown relative to the cell lines. The number of pairs in each quadrant is shown. (B) Expression change of FBS genes (blue) and other genes against normal cells in glioblastoma fresh tissue (left) and in cancer cell lines after a number of passages. At the right, the value for commonly used cell lines is shown. (C) Relative methylation of classifier FBSs in cancer cell lines, fresh cancer tissue, normal cell lines and normal tissue.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120258&req=5

f6: Expression and DNA methylation of cancer cell lines.(A) DNA methylation and expression changes of FBSs in BL cell lines against BL fresh tissues (top left), KARPAS-422 against FL fresh tissues (top right), lymphoma cell lines against normal germinal center B-cells (bottom left) and germinal center B-cells against FL fresh tissues. Changes are shown relative to the cell lines. The number of pairs in each quadrant is shown. (B) Expression change of FBS genes (blue) and other genes against normal cells in glioblastoma fresh tissue (left) and in cancer cell lines after a number of passages. At the right, the value for commonly used cell lines is shown. (C) Relative methylation of classifier FBSs in cancer cell lines, fresh cancer tissue, normal cell lines and normal tissue.
Mentions: Earlier cell line based studies of hypermethylation in bivalent regions did not report an up-regulation of associated genes15. To investigate this discrepancy, we compared DNA methylation16 and gene expression40414243 of lymphoma cell lines to fresh cancer tissue and normal control cells. Indeed, our comparison revealed a hypermethylation of bivalent regions accompanied by a down-regulation of associated genes in the cell lines when compared to fresh cancer tissues (Fig. 6A). Our re-analysis of expression data of a glioblastoma cell line freshly generated by Lee et al.44 indicated that FBS genes are gradually silenced with each passage. After a couple of passages, FBS genes show an expression profile close to that in control cells and other established cell lines (Fig. 6B). We could confirm the repression of FBS genes in independent data from cervix carcinoma cell lines45 and also found a small but significant (p < 0.008) reduction of FBS gene expression in freshly generated cell lines from lung carcinoma metastasis46 (Supplementary Fig. S10). We also investigated whether the relative classifier CpG methylation of cell lines is different to the one of primary tissues. Cancer cell lines (but not normal cell lines) showed a significantly higher relative descriptor CpG methylation than fresh cancer tissues (p < 10−13, Fig. 6C).

View Article: PubMed Central - PubMed

ABSTRACT

Bivalent (poised or paused) chromatin comprises activating and repressing histone modifications at the same location. This combination of epigenetic marks at promoter or enhancer regions keeps genes expressed at low levels but poised for rapid activation. Typically, DNA at bivalent promoters is only lowly methylated in normal cells, but frequently shows elevated methylation levels in cancer samples. Here, we developed a universal classifier built from chromatin data that can identify cancer samples solely from hypermethylation of bivalent chromatin. Tested on over 7,000 DNA methylation data sets from several cancer types, it reaches an AUC of 0.92. Although higher levels of DNA methylation are often associated with transcriptional silencing, counter-intuitive positive statistical dependencies between DNA methylation and expression levels have been recently reported for two cancer types. Here, we re-analyze combined expression and DNA methylation data sets, comprising over 5,000 samples, and demonstrate that the conjunction of hypermethylation of bivalent chromatin and up-regulation of the corresponding genes is a general phenomenon in cancer. This up-regulation affects many developmental genes and transcription factors, including dozens of homeobox genes and other genes implicated in cancer. Thus, we reason that the disturbance of bivalent chromatin may be intimately linked to tumorigenesis.

No MeSH data available.


Related in: MedlinePlus