Lsh is required for meiotic chromosome synapsis and retrotransposon silencing in female germ cells

Abstract

Lymphoid specific helicase (Lsh) is a major epigenetic regulator that is essential for DNA methylation and transcriptional silencing of parasitic elements in the mammalian genome. However, whether Lsh is involved in the regulation of chromatin-mediated processes during meiosis is not known. Here, we show that Lsh is essential for the completion of meiosis and transcriptional repression of repetitive elements in the female gonad. Oocytes from Lsh knockout mice exhibit demethylation of transposable elements and tandem repeats at pericentric heterochromatin, as well as incomplete chromosome synapsis associated with persistent RAD51 foci and gammaH2AX phosphorylation. Failure to load crossover-associated foci results in the generation of non-exchange chromosomes. The severe oocyte loss observed and lack of ovarian follicle formation, together with the patterns of Lsh nuclear compartmentalization in the germ line, demonstrate that Lsh has a critical and previously unidentified role in epigenetic gene silencing and maintenance of genomic stability during female meiosis.

Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation

“…Similar studies in human embryonic fibroblasts demonstrated that 5-azadeoxycytidine-induced loss of DNA methylation resulted in derepression of LINE-1 [45]. In addition, deletion of the DNA methyltransferase 3L (Dnmt3l) or lymphoid-specific helicase (Lsh) gene results in the loss of DNA methylation on TEs and the derepression of TEs in germ cells [16,17,19]. Furthermore, an in vitro study suggested that DNA methylation on LINE-1 promoter is essential for inhibition of LINE-1 expression [20].…”

“…About 40% of the mouse genome is composed of TEs, including long interspersed nucleotide elements (LINEs), short interspersed nucleotide elements (SINEs), and LTR retrotransposable elements [15]. Since expression of TEs can result in their translocation into the host genome, leading to the disruption of genome integrity [16,17], they are silenced in most cell types. A major epigenetic mechanism used in silencing TEs is DNA methylation [14].…”

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

“…In this case, the two sexes are equally susceptible to TE reactivation in their germlines and share common defense mechanisms (Brennecke et al, 2007;Aravin et al, 2007a). The only known case of potential TE reactivation in mammalian oocytes is reported for female mice bearing mutations in the Lsh helicase gene, a regulator of DNA methylation (De La Fuente et al, 2006). However, this effect could be secondary to a more general perturbation of embryonic development and the effect on fertility is not known.…”

“…Among them, Lsh (lymphoid-specific helicase) is a member of the SNF2 family of chromatin remodeling ATPases that facilitates the access of Dnmts to the DNA substrate (Zhu et al, 2006). Inactivation of Lsh in mice results in decreased methylation and increased expression of IAP elements in female germ cells and in embryonic tissues, which leads to early post-natal lethality (Huang et al, 2004;De La Fuente et al, 2006). To ensure the clonal propagation of methylation patterns upon cellular divisions, the maintenance DNA-methyltransferase Dnmt1 requires UHRF1 to load onto hemi-methylated DNA strands generated by replication (Sharif et al, 2007).…”

Conserved themes in small-RNA-mediated transposon control

“…H3K9 tri-methylation and DNA methylation on centromeric repeats and on some elements are partially dependent on the redundant methyltransferases Suv39h1 and Suv39h2, which are required for transcriptional repression of transposons in embryonic stem cells [117,118]. Additionally, a Ddm1 homolog, Lsh (lymphoid-specific helicase), has been implicated in transposon methylation in embryos and in the female germline [119,120]. Given that both miwi2 and mili knockouts affect transcriptional repression and methylation of L1 and IAP elements [45,86] (A. Girard and G.J.…”