Putative model for DNA methylation-dependent repeat regulation by Lsh during embryonic development. (a) WT background: the early pluripotent embryo is globally hypomethylated compared to the heavily methylated one-cell zygote (which experiences a wave of DNA demethylation shortly after fertilisation). Subsequently, a wave of de novo global DNA methylation mediated by Dnmt3a and Dnmt3b in cooperation with Lsh (and perhaps in part Dnmt1/UHRF1) occurs, thereby re-imposing methylation. At later embryonic stages, Dnmt1 and UHRF1 cooperate to maintain stable DNA methylation patterns as lineages differentiate. (b) Lsh mutant background: in the absence of Lsh, de novo methylation may be perturbed in some cases. Later stage Lsh mutant embryos are presumably unable to target the maintenance methyltransferase Dnmt1 to specific repeat compartments (including LTR-ERV, LINE-1 and satellites), leading to the hypomethylation phenotypes observed in these mutants. (c) Lsh and Dnmt1 are functionally both required to regulate LTR-ERVs (independent of Dnmt3b) in maintaining a highly DNA methylated and H3K9me3 associated chromatin state (left). In the absence of Lsh or Dnmt1, LTR-ERVs have reduced DNA methylation and H3K9me3 levels, are actively transcribed and acquire the activation associated histone modification H3K4me3 (right). SAM: S-adenosyl methionine.