Lsh regulates LTR retrotransposon repression independently of Dnmt3b function
1 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, Scotland
2 Departments of Genetics (Computational Genetics) and Center for Epigenomics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, USA
3 Newcastle Medical School, Framlington Place, Newcastle University, Newcastle Upon Tyne NE2 4HH, England
4 Room 2 M51 Cancer Research Building, Pediatrics and Oncology, Cellular and Molecular Medicine, Johns Hopkins, Baltimore, MD, USA
Genome Biology 2013, 14:R146 doi:10.1186/gb-2013-14-12-r146Published: 24 December 2013
DNA methylation contributes to genomic integrity by suppressing repeat-associated transposition. In addition to the canonical DNA methyltransferases, several auxiliary 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.