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Defending Ourselves by Keeping ‘Junk DNA’ Quiet

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


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