Security and anti-virus software is a must-have accessory for the internet age, but it turns out that DNA methylation has been protecting us all from retroviral infections for quite a bit longer than any computer program. A talented research team lead by Richard Meehan from the University of Edinburgh (Scotland) applied HELP-seq analysis and DNA methylation mutants as a model to investigate how retrotransposon activation is selective and context dependent.
The team scoured the methylome data, and made a number of precise novel observations with respect to the specificity of activation; which classes of repeats are activated in mutants and which are not, and the effect of repeat activation in relation to neighboring genes.
“DNA methylation can act as a protective mechanism that contributes to the transcriptional repression of the murine genome repetitive complement to maintain genomic integrity…in addition to DNA methyltransferases, several chromatin related factors are required to maintain DNA methylation at intergenic and satellite repeats.” Meehan explained.
One of these players is Lymphoid specific helicase (Lsh, a member of the SNF2 superfamily of chromatin helicases) and is required for maintaining the methylation patterns of a developing embryo. Lsh has been shown to interact with the de novo methyltransferase Dnmt3b, which allows it to mastermind the placement of DNA methylation and ultimately cause transcriptional silencing of stem cell associated genes. Given this cooperation between Lsh and Dnmt3b in single copy gene regulation, the group wanted to determine if a similar mechanism exists in repetitive DNA repression. Here’s what was discovered:
- Long Interspersed Nuclear Elements (LINES) that have lost DNA methylation are not activated in two distinct DNA methylation mutant mouse models.
- However, in stark contrast, virus like particles corresponding to the activation of Intracisternal A-type Particles (IAPs, another class of retrotransposon) are 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.
The Methylome Guards Genomic Integrity
The loss of DNA methylation does not automatically lead to gene or repeat activation, but depends on the cellular context, providing a number of implications for the impact of DNA methylation reprogramming pathways in development. Meehan concludes that “Our study emphasises that regulation of specific repetitive elements by DNA methylation is regulated with a high degree of specificity and that this research provides a model where Lsh is required during early development to target de novo methylation at repeat sequences, which is subsequently maintained by the action of Dnmt1 and repressive histone tail modifications in order to…maintain genomic integrity.”
Go get some HELP with your methylome over at Genome Biology, January 2014