Corporate Banner
Satellite Banner
Stem Cells, Cellular Therapy & Biobanking
>
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Non-Genotoxic Carcinogen Exposure Induces Defined Changes in the 5-Hydroxymethylome

Published: Friday, October 05, 2012
Last Updated: Friday, October 05, 2012
Bookmark and Share
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.

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 field of DNA methylation biology has been in a dynamic flux with the publication of new high resolution mapping studies of the DNA methylome in different tissues contexts and by the discovery of new modifications in mammalian DNA, notably a 6th DNA base 5-hydoxymethylcytosine (5hmC). It was recently discovered that 5-methylcytosine (5mC) can be oxidised to 5-hydroxymethylcytosine (5hmC) by the family of ten-eleven translocation (TET) enzymes, and that genomic 5hmC is abundant in a subset of mammalian tissues.  The 5hmC base has been linked to the enigmatic process of DNA demethylation, where the 5mC base is converted to C either through an active or passive mechanism. In a genome wide study Meehan, Moggs and MARCAR co-authors examine the 5mC and 5hmC profiles in liver of control and phenobarbital (PB) treated mice. Essentially they observe dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter of genes that are transcriptionally up-regulated after exposure to phenobarbital. 5hmC had been hypothesized to function as an intermediate of active demethylation during carcinogenesis; this study now provides support for this view.

Summary:

In a genome wide-multi sample study the authors examine the 5mC and 5hmC profiles in liver of control and phenobarbital (PB) treated mice. They observe dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter of genes that are transcriptionally up-regulated after exposure to phenobarbital. This reprogramming of 5mC/5hmC coincides with characteristic changes in the histone marks H3K4me2, H3K27me3 and H3K36me3. Quantitative analysis of phenobarbital-induced genes that are involved in xenobiotic metabolism reveals that both DNA modifications are lost at the transcription start site, while there is a reciprocal relationship between increasing levels of 5hmC and loss of 5mC at regions immediately adjacent to core promoters. Collectively, these experiments support the hypothesis that 5hmC is a potential intermediate in a demethylation pathway and reveal precise perturbations of the mouse liver DNA methylome and hydroxymethylome upon exposure to a rodent hepatocarcinogen.

This study was initiated through funding by the Innovative Medicines Initiative (IMI), a joint initiative (Public-Private Partnership) of the DG Research of the European Commission, representing the European Communities, and the European Federation of Pharmaceutical Industries and Associations (EFPIA). IMI funded a 5 year program, MARCAR, which aims to identify novel bioMARkers and molecular tumor classification for non-genotoxic CARcinogenesis. IMI is aimed towards removing research bottlenecks in the current drug development process.

The new data also contribute to answering some of the provocative questions raised by the National Cancer Institute (http://provocativequestions.nci.nih.gov/rfa) including: 1) ”As modern measurement technologies improve, are there better ways to objectively ascertain exposure to cancer risk?” and 2) “How does susceptibility of exposure to cancer risk factors change during development?”

--------------------------------------------------------------------------------------------------------------------------

Author list: John P Thomson, Harri Lempiäinen, Jamie A Hackett, Colm E Nestor, Arne Müller, Federico Bolognani, Edward J Oakeley, Dirk Schübeler, Rémi Terranova, Diana Reinhardt, Jonathan G Moggs and Richard R Meehan*

Title : Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome

Journal: Genome Biology

http://genomebiology.com/2012/13/10/R93

Summary

Background

Induction and promotion of liver cancer by exposure to non-genotoxic carcinogens coincides with epigenetic perturbations, including specific changes in DNA methylation. Here we investigate the genome-wide dynamics of 5-hydroxymethylcytosine (5hmC) as a likely intermediate of 5-methylcytosine (5mC) demethylation in a DNA methylation reprogramming pathway. We use a rodent model of non-genotoxic carcinogen exposure using the drug phenobarbital.

Results

Exposure to phenobarbital results in dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter regions of a cohort of genes that are transcriptionally upregulated. This reprogramming of 5mC/5hmC coincides with characteristic changes in the histone marks H3K4me2, H3K27me3 and H3K36me3. Quantitative analysis of phenobarbital-induced genes that are involved in xenobiotic metabolism reveals that both DNA modifications are lost at the transcription start site, while there is a reciprocal relationship between increasing levels of 5hmC and loss of 5mC at regions immediately adjacent to core promoters.

Conclusions

Collectively, these experiments support the hypothesis that 5hmC is a potential intermediate in a demethylation pathway and reveal precise perturbations of the mouse liver DNA methylome and hydroxymethylome upon exposure to a rodent hepatocarcinogen.


Further Information

Join For Free

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 3,000+ scientific posters on ePosters
  • More than 4,500+ 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 TechnologyNetworks.com 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

Unanticipated Consequences of DNA Hypomethylation; Loss and Gain of Polycomb Mediated Transcription Repression in Somatic Cells
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.
Monday, April 01, 2013
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
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
Turning Skin Cells into Heart, Brain Cells
In a major breakthrough, scientists at the Gladstone Institutes transformed skin cells into heart cells and brain cells using a combination of chemicals.
Stem Cells Know How to Unwind
Research led by the Babraham Institute with collaborators in the UK, Canada and Japan has revealed a new understanding of how an open genome structure supports the long-term and unrestricted developmental potential in embryonic stem cells.
Growing Stem Cells More Safely
Nurturing stem cells atop a bed of mouse cells works well, but is a non-starter for transplants to patients – Brown University scientists are developing a synthetic bed instead.
Cell Transplant Treats Parkinson’s in Mice
A University of Wisconsin—Madison neuroscientist has inserted a genetic switch into nerve cells so a patient can alter their activity by taking designer drugs that would not affect any other cell.
Skin Cells Turned into Heart Cells and Brain Cells Using Drugs
In a scientific first, Gladstone researchers have used chemical drugs to convert skin cells into heart cells and brain cells, without adding any external genes.
Shape Of Tumor May Affect Whether Cells Can Metastasize
Illinois researchers found that the shape of a tumor may play a role in how cancer cells become primed to spread.
‘Mini-Brains’ to Study Zika
Novel tool expected to speed research on brain and drug development.
Cytokine Triggers Immune Response at Expense of Blood Renewal
Research highlights promise of Anti-IL-1 drugs to treat chronic inflammatory disease.
AstraZeneca to Sequence 2 Million Genomes in Search for New Drugs
Company launches integrated genomics approach which aims to transform drug discovery and development.
Improving Engineered T-Cell Cancer Treatment
Purdue University researchers may have figured out a way to call off a cancer cell assassin that sometimes goes rogue and assign it a larger tumor-specific "hit list."
SELECTBIO

SELECTBIO Market Reports
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
3,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,500+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!