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

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

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 2,600+ scientific posters on ePosters
  • More than 3,800+ 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

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
HIV Patients Should Be Included in Early Clinical Trials of Anti-TB Drugs
Tuberculosis is the number one cause of death in HIV-infected patients in Africa and a leading cause of death in this population worldwide.
Multi-Gene Test Enables Some Breast Cancer Patients to Safely Avoid Chemotherapy
A major study is providing the best evidence to date that a 21-gene test done on the tumor can identify breast cancer patients who can safely avoid chemotherapy.
Low Dose Beta-Blockers As Effective As High Dose After a Heart Attack?
Heart attack patients live as long – or even longer – on one-quarter the suggested dose.
Antidepressants Plus Blood-Thinners Slow Down Brain Cancer
EPFL scientists have found that combining antidepressants with anticoagulants slows down brain tumors (gliomas) in mice.
Old Drug Performs New Tricks
Cambridge-led research reveals the powers of a "wonder drug" that has lain under the noses of doctors for 50 years.
Electronic Reminders Keep TB Patients on Track With Medication In China
Giving electronic reminders to tuberculosis (TB) patients in China can reduce the amount of medication doses they miss by half, according to new research.
Common Drug Presents Fracture Risk To Older Women
Researchers are urging caution in prescribing one of the world’s most commonly issued drug groups, citing links to increased fracture risks in older Australian women.
Combining Epigenetic Therapies and Immunotherapies Improves Cancer Outcomes
Recent data suggest that epigenetic therapies are likely to provide additional clinical benefit to cancer patients when rationally combined with immunotherapeutic drugs.
LiMAx Test Shows Reversibility of Fatty Liver Disease After Obesity Surgery
Clinical study provides evidence for functional liver recovery after weight loss.
Landmark NIH Study Shows Intensive Blood Pressure Management May Save Lives
Lower blood pressure target greatly reduces cardiovascular complications and deaths in older adults.
Scroll Up
Scroll Down

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
2,600+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos