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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

Hypermethylation of bivalent chromatin in cancer tissues.(A) Loss of bivalency is associated to hypermethylation. DNA methylation change of bivalent segments in relation to their stability. DNA methylation change for fresh cancer (left) and cancer cell lines (right) is shown for all elements in the cells of origin. Violet: chromatin bivalent in cancer and cell of origin, blue: chromatin no longer bivalent in cancer, grey: chromatin bivalent in cancer but not in cell of origin. (B) Bivalent chromatin regions show highest hypermethylation. DNA methylation difference for the 15 Roadmap chromatin states in BL. Bivalent states (grey box) show the strongest hypermethylation. (C) FBS regions are hypermethylated along their whole length. DNA methylation difference in BL at (grey marked area) and around FBSs, shown for FBSs > 10,000 nt (black), FBSs < 10,000 nt (blue), FBS sub-segments bivalent in primary B cells (red) and segments bivalent in primary B cells but not overlapping FBS (brown). (D) Methylation of bivalent regions is a good descriptor of cancer. ROC curve using relative descriptor methylation of FBSs (orange), bivalent enhancer (black), bivalent promoters (green), polycomb repressed regions without FBS (ocher) and ESC derived classifier (blue).
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f3: Hypermethylation of bivalent chromatin in cancer tissues.(A) Loss of bivalency is associated to hypermethylation. DNA methylation change of bivalent segments in relation to their stability. DNA methylation change for fresh cancer (left) and cancer cell lines (right) is shown for all elements in the cells of origin. Violet: chromatin bivalent in cancer and cell of origin, blue: chromatin no longer bivalent in cancer, grey: chromatin bivalent in cancer but not in cell of origin. (B) Bivalent chromatin regions show highest hypermethylation. DNA methylation difference for the 15 Roadmap chromatin states in BL. Bivalent states (grey box) show the strongest hypermethylation. (C) FBS regions are hypermethylated along their whole length. DNA methylation difference in BL at (grey marked area) and around FBSs, shown for FBSs > 10,000 nt (black), FBSs < 10,000 nt (blue), FBS sub-segments bivalent in primary B cells (red) and segments bivalent in primary B cells but not overlapping FBS (brown). (D) Methylation of bivalent regions is a good descriptor of cancer. ROC curve using relative descriptor methylation of FBSs (orange), bivalent enhancer (black), bivalent promoters (green), polycomb repressed regions without FBS (ocher) and ESC derived classifier (blue).

Mentions: As DNA at bivalent chromatin is usually very lowly methylated, we suspected that the hypermethylation of bivalent chromatin in normal cells is accompanied by the loss of bivalency. A previous report on the correlation of hypermethylation with the loss of cancer related promoters in fresh gastric cancer26, is in line with this assumption. To further test this hypothesis, we compared the DNA methylation changes of chromatin state segments that lost their bivalent state in cancer cell lines to those that stayed bivalent or were only bivalent in cancer cell lines. This test included cell lines for five different types of cancer. In all data sets, hypermethylation of regions that lost their bivalency was significantly stronger (p < 10−9) than for stably bivalent regions, indicating that hypermethylation might indeed be associated with the loss of bivalency. On average, new bivalent regions did not show hypermethylation (Fig. 3A).


Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer
Hypermethylation of bivalent chromatin in cancer tissues.(A) Loss of bivalency is associated to hypermethylation. DNA methylation change of bivalent segments in relation to their stability. DNA methylation change for fresh cancer (left) and cancer cell lines (right) is shown for all elements in the cells of origin. Violet: chromatin bivalent in cancer and cell of origin, blue: chromatin no longer bivalent in cancer, grey: chromatin bivalent in cancer but not in cell of origin. (B) Bivalent chromatin regions show highest hypermethylation. DNA methylation difference for the 15 Roadmap chromatin states in BL. Bivalent states (grey box) show the strongest hypermethylation. (C) FBS regions are hypermethylated along their whole length. DNA methylation difference in BL at (grey marked area) and around FBSs, shown for FBSs > 10,000 nt (black), FBSs < 10,000 nt (blue), FBS sub-segments bivalent in primary B cells (red) and segments bivalent in primary B cells but not overlapping FBS (brown). (D) Methylation of bivalent regions is a good descriptor of cancer. ROC curve using relative descriptor methylation of FBSs (orange), bivalent enhancer (black), bivalent promoters (green), polycomb repressed regions without FBS (ocher) and ESC derived classifier (blue).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Hypermethylation of bivalent chromatin in cancer tissues.(A) Loss of bivalency is associated to hypermethylation. DNA methylation change of bivalent segments in relation to their stability. DNA methylation change for fresh cancer (left) and cancer cell lines (right) is shown for all elements in the cells of origin. Violet: chromatin bivalent in cancer and cell of origin, blue: chromatin no longer bivalent in cancer, grey: chromatin bivalent in cancer but not in cell of origin. (B) Bivalent chromatin regions show highest hypermethylation. DNA methylation difference for the 15 Roadmap chromatin states in BL. Bivalent states (grey box) show the strongest hypermethylation. (C) FBS regions are hypermethylated along their whole length. DNA methylation difference in BL at (grey marked area) and around FBSs, shown for FBSs > 10,000 nt (black), FBSs < 10,000 nt (blue), FBS sub-segments bivalent in primary B cells (red) and segments bivalent in primary B cells but not overlapping FBS (brown). (D) Methylation of bivalent regions is a good descriptor of cancer. ROC curve using relative descriptor methylation of FBSs (orange), bivalent enhancer (black), bivalent promoters (green), polycomb repressed regions without FBS (ocher) and ESC derived classifier (blue).
Mentions: As DNA at bivalent chromatin is usually very lowly methylated, we suspected that the hypermethylation of bivalent chromatin in normal cells is accompanied by the loss of bivalency. A previous report on the correlation of hypermethylation with the loss of cancer related promoters in fresh gastric cancer26, is in line with this assumption. To further test this hypothesis, we compared the DNA methylation changes of chromatin state segments that lost their bivalent state in cancer cell lines to those that stayed bivalent or were only bivalent in cancer cell lines. This test included cell lines for five different types of cancer. In all data sets, hypermethylation of regions that lost their bivalency was significantly stronger (p < 10−9) than for stably bivalent regions, indicating that hypermethylation might indeed be associated with the loss of bivalency. On average, new bivalent regions did not show hypermethylation (Fig. 3A).

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