Corporate Banner
Satellite Banner
RNAi
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
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 2,500+ scientific posters on ePosters
  • More than 3,700+ 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

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
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
Scientific News
Liquid Biopsies: Utilization of Circulating Biomarkers for Minimally Invasive Diagnostics Development
Market Trends in Biofluid-based Liquid Biopsies: Deploying Circulating Biomarkers in the Clinic. Enal Razvi, Ph.D., Managing Director, Select Biosciences, Inc.
Watching a Tumour Grow in Real-Time
Researchers from the University of Freiburg have gained new insight into the phases of breast cancer growth.
Childhood Cancer Cells Drain Immune System’s Batteries
Cancer cells in neuroblastoma contain a molecule that breaks down a key energy source for the body’s immune cells, leaving them too physically drained to fight the disease.
Urine Proteins Point to Early-Stage Pancreatic Cancer
A combination of three proteins found at high levels in urine can accurately detect early-stage pancreatic cancer, researchers at the BCI have shown.
Researcher Discovers Trigger of Deadly Melanoma
New research sheds light on the precise trigger that causes melanoma cancer cells to transform from non-invasive cells to invasive killer agents, pinpointing the precise place in the process where "traveling" cancer turns lethal.
Self-Assembling, Biomimetic Membranes May Aid Water Filtration
A synthetic membrane that self assembles and is easily produced may lead to better gas separation, water purification, drug delivery and DNA recognition, according to an international team of researchers.
Error Correction Mechanism in Cell Division
Cell biologists have reported an advance in understanding the workings of an error correction mechanism that helps cells detect and correct mistakes in cell division early enough to prevent chromosome mis-segregation and aneuploidy, that is, having too many or too few chromosomes.
Researchers Resurrect Ancient Viruses
Researchers at Massachusetts Eye and Ear and Schepens Eye Research Institute have reconstructed an ancient virus that is highly effective at delivering gene therapies to the liver, muscle, and retina.
Cell Aging Slowed by Putting Brakes on Noisy Transcription
Experiments in yeast hint at ways to extend life of some human cells.
Crucial for Stem Cell Survival Protein Identified Using Editing Tool CRISPR
A team of University of Wisconsin-Madison engineers has identified a protein that is integral to the survival and self-renewal processes of human pluripotent stem cells (hPSC).
SELECTBIO

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
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!