Corporate Banner
Satellite Banner
AgriGenomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Defending Ourselves by Keeping ‘Junk DNA’ Quiet

Published: Wednesday, January 01, 2014
Last Updated: Monday, January 06, 2014
Bookmark and Share
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.

Protein coding genes only account for about 2% of mammalian genomes, whilst repetitive DNA sequences occupy about 50%. One of the major drivers of genetic change in the genome are highly abundant mobile retrotransposon elements. It is in the host’s interest to suppress these potentially dangerous retrotransposons using genome defence mechanisms. One such repressive mechanism is thought to act via DNA methylation, a chemical modification of DNA that is associated with transcriptional inactivity.

In this latest study in Genome Biology , Dunican and colleagues have revealed the range and profile of retrotransposon activation in the absence of a putative chromatin remodelling factor, Lsh, that is required for setting up methylation patterns in mouse development. Using DNA methylation mutants, they find that surprisingly, retrotransposon activation is selective and context dependent. Long Intersperced Nuclear Elements (LINES) that have lost DNA methylation are not activated in two distinct DNA methylation mutant mouse models. In stark contrast, virus like particles corresponding to the activation of IAP elements (another class of retrotransposon) linked to DNA methylation losses can be observed in both DNA methylation mutant models. Moreover, distinct IAPs are selectively activated in either mutant type, implying that activation of this class of retrotransposons is not general but discriminatory. This work highlights that loss of DNA methylation does not automatically lead to gene or repeat activation but depends on the cellular context. The results have important implications for the impact of DNA methylation reprogramming pathways in development and disease, especially cancer where for example endogenous retrotransposition is an important etiological factor in human liver cancer.
 
This study was funded by the Medical Research Council.
 
Abstract:
DNA methylation contributes to genomic integrity by suppressing repeat-associated transposition. In addition to the canonical DNA methyltransferases, several auxillary chromatin factors are required to maintain DNA methylation at intergenic and satellite repeats. The interaction between Lsh, a chromatin helicase, and the de novo methyltransferase Dnmt3b facilitates deposition of DNA methylation at stem cell genes, which are hypomethylated in Lsh-/- embryos. We wished to determine if a similar targeting mechanism operates to maintain DNA methylation at repetitive sequences.

We mapped genome-wide DNA methylation patterns in Lsh-/- and Dnmt3b-/- somatic cells. DNA methylation is predominantly lost from specific genomic repeats in Lsh-/- cells: LTR-retrotransposons, LINE-1 repeats and mouse satellites. RNA-seq experiments demonstrate that specific IAP LTRs and satellites, but not LINE-1 elements, are aberrantly transcribed in Lsh-/- cells. LTR hypomethylation in Dnmt3b-/- cells is moderate, whereas IAP, LINE-1 and satellite elements are hypomethylated but silent. Repressed LINE-1 elements in Lsh-/- cells gain H3K4me3, but H3K9me3 levels are unaltered, indicating that DNA hypomethylation alone is not permissive for their transcriptional activation. Mis-expressed IAPs and satellites lose H3K9me3 and gain H3K4me3 in Lsh-/- cells.

Our study emphasizes that regulation of repetitive elements by Lsh and DNA methylation is selective and context dependent. Silencing of repeats in somatic cells appears not to be critically dependent on Dnmt3b function. We propose a model where Lsh is specifically required at a precise developmental window to target de novo methylation to repeat sequences, which is subsequently maintained by Dnmt1 to enforce selective repeat silencing.
 
Funding: 
This study was funded by the Medical Research Council (UK) at the MRC Human Genetics Unit at the IGMM  in Edinburgh University.


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 3,200+ scientific posters on ePosters
  • More than 4,700+ 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

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
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
Open Source Seed Initiative – A Welcome Boost to Global Crop Breeding
A team of plant breeders, farmers, non-profit agencies, seed advocates, and policymakers have created the Open Source Seed Initiative.
Four Newly-Identified Genes Could Improve Rice
A Japanese research team have applied a method used in human genetic analysis to rice and rapidly discovered four new genes that are potentially significant for agriculture. These findings could influence crop breeding and help combat food shortages caused by a growing population.
“Amazing Protein Diversity” Discovered in Maize
The genome of the corn plant – or maize, as it’s called almost everywhere except the US – “is a lot more exciting” than scientists have previously believed. So says the lead scientist in a new effort to analyze and annotate the depth of the plant’s genetic resources.
Invasive Species Could Cause Billions in Agriculture Damages
Invasive insects and pathogens could be a multi-billion-dollar threat to global agriculture and developing countries may be the biggest target, according to a team of international researchers.
Genetic Research Can Significantly Improve Drug Development
With drug development costs topping $1.2bn (£850 million) to get a single treatment to the point it can be sold and used in the clinic, could genetic analysis save hundreds of millions of dollars?
What Makes a Good Scientist?
It’s the journey, not just the destination that counts as a scientist when conducting research.
Scoliosis Linked to Disruptions in Spinal Fluid Flow
A new study in zebrafish suggests that irregular fluid flow through the spinal column brought on by gene mutations is linked to a type of scoliosis that can affect humans during adolescence.
More Research Needed to Ensure Gene Drive Safety
Gene-Drive modified organisms are not ready to be released into environment a new report calls for more research and robust assessment.
Genetic Basis of Petunia Variation Uncovered
A large international team of researchers, including scientists from Wageningen University, have now sequenced the entire genome of two different wild petunia species, and published this in the important scientific journal Nature Plants.
Genetically Engineered Crops Are Safe
Distinction between genetic engineering and conventional plant breeding becoming less clear, says new report on GE crops.
Skyscraper Banner

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
3,200+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!