title: Lsh regulates LTR retrotransposon repression independently of Dnmt3b function.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Donncha S
authors.initials: DS
authors.lastname: Dunican
authors.forename: Hazel A
authors.initials: HA
authors.lastname: Cruickshanks
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.forename: Colin A
authors.initials: CA
authors.lastname: Semple
authors.forename: Tracey
authors.initials: T
authors.lastname: Davey
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Arceci
authors.forename: John
authors.initials: J
authors.lastname: Greally
authors.forename: Ian R
authors.initials: IR
authors.lastname: Adams
authors.forename: Richard R
authors.initials: RR
authors.lastname: Meehan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics*; D019175:DNA Methylation; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology; D006657:Histones / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D018626:Retroelements; D017422:Sequence Analysis, DNA; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D004265:DNA Helicases; D006657:Histones; D018626:Retroelements; D000097584:DNA Methyltransferase 3B; C491758:lymphoid specific helicase, mouse