Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jun 15;12(12):1835-41.
doi: 10.4161/cc.25010. Epub 2013 May 15.

Tight correlation of 5-hydroxymethylcytosine and Polycomb marks in health and disease

Michael C Haffner  1 , Laxmi G Pellakuru, Susmita Ghosh, Tamara L Lotan, William G Nelson, Angelo M De Marzo, Srinivasan Yegnasubramanian
Affiliations

Tight correlation of 5-hydroxymethylcytosine and Polycomb marks in health and disease

Michael C Haffner et al. Cell Cycle. .

Abstract

Modifications to DNA and histone tails represent key epigenetic marks involved in establishing and maintaining cell identity and can be dysregulated in human diseases, including cancer. Two such modifications, tri-methylation of lysine-27 on histone H3 (H3K27me3) mediated by the Polycomb complex and hydroxymethylation of cytosines on DNA, have recently been shown to be dynamically regulated during differentiation. Here, we show that global levels of 5-hydroxymethylcytosine (5hmC) and H3K27me3 are highly correlated across a variety of somatic tissues. In multiple hierarchically organized tissues, both marks showed almost identical cell-by-cell distribution patterns that exhibited a tight association with differentiation. In particular, tissue stem cell compartments were characterized by low levels of both marks, whereas differentiated cell compartments exhibited high levels of 5hmC and H3K27me3. This pattern of correlation between the two marks could be recapitulated in an in vitro model system of induced differentiation in prostate epithelial cells. While the correlation between 5hmC and H3K27me3 levels is also maintained in human cancers, the degree of correlation is reduced. These findings suggest a previously unappreciated link between 5hmC and H3K27me3 regulation that should be explored in future mechanistic studies.

Keywords: 5-hydroxymethylcytosine; DNA methylation; H3K27me3; cancer; differentiation; epigenetics; polycomb.

PubMed Disclaimer

Figures

None
Figure 1. 5hmC and H3K27me3 show highly similar distribution patterns in colonic mucosa. To evaluate the distribution of 5hmC and H3K27me3 in the colonic mucosa, adjacent sections of formalin-fixed paraffin-embedded colonic tissues were stained with 5hmC and H3K27me3-specific antibodies. Note that terminally differentiated epithelial cells toward the lumen of the colon (arrowheads) show strong staining for 5hmC and H3K27me3, whereas cells in the crypts (arrows) show very low levels of 5hmC and H3K27me3.
None
Figure 2. Immunofluorescence double labeling reveals a high degree of co-localization of 5hmC and H3K27me3 in differentiated adult tissues. Tissue sections containing normal prostate epithelium, lymphoid tissue and testis were co-immunolabeled with antibodies specific to 5hmC (shown in green) and H3K27me3 (shown in red). (A) In normal prostate epithelium, 5hmC and H3K27me3 are present at high levels in the terminally differentiated luminal cells (arrowheads). Note that basal cells (arrows) exhibit greatly decreased staining intensities for both marks. (B) In the activated lymph follicle, 5hmC and H3K27me3 are both present with very high concordance in distinct cell populations in the germinal center (arrowheads) and the marginal zone (arrows). (C) In cross sections of the human testis, 5hmC and H3K27me3 are present in Sertoli cells in the seminal tubules (arrowheads) and in stromal cells surrounding the tubuli (arrows), but not in spermatogonia or mature spermatids.
None
Figure 3. In vitro differentiation of prostate epithelial cells is associated with increased 5hmC and H3K27me3 levels. RWPE-1 prostate epithelial cells showed a basal cell like phenotype characterized by the absence of androgen receptor (AR) expression and low to undetectable levels of 5hmC and H3K27me3 when cultured under standard 2D culturing conditions. (A) Introduction of RWPE-1 cells in a 3D matrigel matrix induced formation of highly organized acinar structures (arrows) and ductal branching (arrowheads). This morphological differentiation was associated with an increase in AR levels and accumulation of 5hmC and H3K27me3 (arrows). (B) shows representative micrographs of cross sections obtained from 2D cultures and 3D cultures. Note the high level of AR, 5hmC and H3K27me3 staining in the acinar epithelial structures formed in 3D cultures (arrows).
None
Figure 4. 5hmC and H3K27me3 levels are decreased in cancers. (A) Prostate adenocarcinoma (arrows) showed global decreased levels of 5hmC and H3K27me3 as compared to normal prostate luminal cells (arrowheads). Similarly, neoplastic cells in breast (B), colon (C) and pancreatic adenocarcinoma (D) (arrows) were characterized by reduced 5hmC and H3K27me3 staining levels. Tumor associated stromal cells (arrowheads) showed high levels of 5hmC and H3K27me3. Note that the degree of loss between adjacent normal tissue and cancer cells was more pronounced for 5hmC and the correlation of 5hmC and H3K27me3 is less pronounced.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007;447:425–32. doi: 10.1038/nature05918. - DOI - PubMed
    1. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148–59. doi: 10.1056/NEJMra072067. - DOI - PubMed
    1. Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer. 2004;4:143–53. doi: 10.1038/nrc1279. - DOI - PubMed
    1. Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev. 2011;25:1010–22. doi: 10.1101/gad.2037511. - DOI - PMC - PubMed
    1. Wyatt GR, Cohen SS. The bases of the nucleic acids of some bacterial and animal viruses: the occurrence of 5-hydroxymethylcytosine. Biochem J. 1953;55:774–82. - PMC - PubMed

Publication types

LinkOut - more resources