Corporate Banner
Satellite Banner
Genotyping & Gene Expression
Scientific Community
Become a Member | Sign in
Home>News>This Article

Unanticipated Consequences of DNA Hypomethylation; Loss and Gain of Polycomb Mediated Transcription Repression in Somatic Cells

Published: Monday, April 01, 2013
Last Updated: Monday, April 01, 2013
Bookmark and Share
By genome-wide mapping of the Polycomb Repressive Complex 2 (PRC2)-signature histone mark, H3K27me3, in DNA methylation-deficient mouse somatic cells, the Meehan lab shows that loss of DNA methylation is coincident with widespread H3K27me3 redistribution.

Unanticipated consequences of DNA hypomethylation; loss and gain of Polycomb mediated transcription repression in somatic cells.

Text book DNA biology describes a genetic code comprising of four DNA bases (A,C,T,G ) and a 5th chemically modified (methylated) base 5-methylcytosine (5mC). The presence of the 5mC base at cytosine rich gene promoters (CpG islands) is highly correlated with transcriptional silencing. Non-methylated CpG island genes are usually highly expressed in cells, but a fraction of these genes can be regulated by a separate regulatory system that does not involve 5mC, termed Polycomb. In this case instead of adding a modification to DNA, it can add methyl groups to a protein closely associated with DNA that also results in gene silencing. Specifically lysine 27 (K27) on histone H3 becomes tri-methylated resulting in H3K27me3 at silenced CpG islands. Polycomb and DNA methylation have always been thought to work independently at CpG islands. However a genome wide study by Reddington, Meehan and co-authors suggests that these mechanisms are more closely linked than previously appreciated. Meehan and co-authors examined the 5mC and histone H3K27me3 profile in cells that have reduced levels of DNA methylation. Essentially they observed many normally non-5mC marked CpG island genes loose Polycomb marks in hypomethylated cells; leading to gene activation without changes in DNA methylation. This accounts for around a third of the increased expression observed in hypomethylated cells, suggesting that participating in Polycomb mediated repression is also a major function for DNA methylation in gene regulation. They hypothesise that loss of methylation throughout the genome creates new, more attractive, ‘landing sites’ for Polycomb. They show that in the hypomethylated cells the Polycomb repression machinery migrates to these new landing sites and can cause de novo silencing of adjacent genes. Frequent observations in cancers are DNA hypomethylation of large genomic domains and hypermethylation of CpG islands. It will be intriguing to investigate the effect of DNA methylation redistribution on Polycomb targeting in cancer cells, and its downstream effect on gene expression. Indeed, new domains of H3K27me3 have been observed in breast cancer cell lines in regions that become DNA hypomethylated.

 A systems level understanding of chromatin structure requires a detailed comprehension of the functional relationships between epigenetic mechanisms, in addition to the roles of the individual mechanisms themselves. The Meehan lab undertook a systematic genomics approach to investigate the emerging functional relationships between DNA methylation and the Polycomb repressor system; two essential epigenetic mechanisms involved in the gene silencing. By genome-wide mapping of the Polycomb Repressive Complex 2 (PRC2)-signature histone mark, H3K27me3, in DNA methylation-deficient mouse somatic cells, James Reddington and colleagues show that loss of DNA methylation leads to widespread H3K27me3 redistribution, consistent with the DNA methylome being an important factor in the targeting of the PRC2 complex throughout the genome. Unexpectedly, in addition to increased H3K27me3 at previously highly DNA methylated genomic regions, they observe a striking loss of H3K27me3 and PRC2 from its normal target gene promoters, including Hox gene clusters. Importantly, we show that many of these genes become ectopically expressed in DNA methylation-deficient cells, consistent with loss of Polycomb-mediated gene repression. They propose that an intact DNA methylome is required for appropriate Polycomb-mediated gene repression by constraining PRC2 targeting. These observations identify a novel functional relationship between DNA methylation and the Polycomb system in gene regulation and will influence our understanding of how these epigenetic mechanisms contribute to normal development and disease.

This study was funded by the Medical Research Council (UK) at the MRC Human Genetics Unit at the IGMM in at Edinburgh University.


Author list
James P. Reddington, Sara M. Perricone, Colm E. Nestor, Judith Reichmann, Neil A. Youngson, Masako Suzuki, Diana Reinhardt, Donncha S. Dunican, James G. Prendergast, Heidi Mjoseng, Bernard H. Ramsahoye, Emma Whitelaw, John M. Greally, Ian R. Adams, Wendy A. Bickmore and Richard R Meehan* Title : Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of polycomb-target genes.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Defending Ourselves by Keeping ‘Junk DNA’ Quiet
By genome-wide mapping in two mutant cell lines, the Meehan lab shows that loss of DNA methylation is coincident with specific activation of the IAP endogenous retroposon and the appearance of virus like particles.
Wednesday, January 01, 2014
Tissue of Origin Determines Cancer-associated CpG Island Promoter Hypermethylation Patterns
Meehan, Sproul and co-workers conclude that general aberrant promoter hypermethylation in cancer does not promote tumorigenesis, but instead reinforces transcription repression inherited from pre-cancerous tissue.
Friday, October 05, 2012
Non-Genotoxic Carcinogen Exposure Induces Defined Changes in the 5-Hydroxymethylome
In a genome wide study Meehan, Moggs and MARCAR co-authors examined 5mC and 5hmC profiles of liver in control and phenobarbital treated mice. They observe dynamic and reciprocal changes in the 5mC/5hmC patterns over genes promoters that are transcriptionally up-regulated.
Friday, October 05, 2012
Coupling Genome Defence to Epigenetic Reprogramming
The work, just published in Development, identifies genes DIRECTLY regulated by DNA methylation.
Thursday, September 06, 2012
Scientific News
Genetic Basis of Fatal Flu Side Effect Discovered
A group of people with fatal H1N1 flu died after their viral infections triggered a deadly hyperinflammatory disorder in susceptible individuals with gene mutations linked to the overactive immune response, according to a recent study.
New Class of RNA Tumor Suppressors Identified
Two short, “housekeeping” RNA molecules block cancer growth by binding to an important cancer-associated protein called KRAS. More than a quarter of all human cancers are missing these RNAs.
Mathematical Model Forecasts the Path of Breast Cancer
Chances of survival depend on which organs breast cancer tumors colonize first.
Ancient Viral Molecules Essential for Human Development
Genetic material from ancient viral infections is critical to human development, according to researchers at the Stanford University School of Medicine.
Measuring microRNAs in Blood to Speed Cancer Detection
A simple, ultrasensitive microRNA sensor holds promise for the design of new diagnostic strategies and, potentially, for the prognosis and treatment of pancreatic and other cancers.
Personalized Drug Screening for Multiple Myeloma Patients
A personalized method for testing the effectiveness of drugs that treat multiple myeloma may predict quickly and more accurately the best treatments for individual patients with the bone marrow cancer.
Metabolic Profiles Distinguish Early Stage Ovarian Cancer with Unprecedented Accuracy
Studying blood serum compounds of different molecular weights has led scientists to a set of biomarkers that may enable development of a highly accurate screening test for early-stage ovarian cancer.
New Way to Force Stem Cells to Become Bone Cells
Potential therapies based on this discovery could help people heal bone injuries or set hardware, such as replacement knees and hips.
Promise of Newborn Stem Cells to Revolutionize Clinical Practice
In this article Shweta Sharma, PhD, discusses the potential of an Umbilical Cord Blood bank as an untapped source of samples for research and clinical trials.
New Anti-Malarial Drug Screening Model
University of South Florida researchers demonstrate novel chemogenomic profiling to identify drug targets for the most lethal strain of malaria.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos