Lsh, an epigenetic guardian of repetitive elements

Abstract

The genome is burdened with repetitive sequences that are generally embedded in silenced chromatin. We have previously demonstrated that Lsh (lymphoid-specific helicase) is crucial for the control of heterochromatin at pericentromeric regions consisting of satellite repeats. In this study, we searched for additional genomic targets of Lsh by examining the effects of Lsh deletion on repeat regions and single copy gene sequences. We found that the absence of Lsh resulted in an increased association of acetylated histones with repeat sequences and transcriptional reactivation of their silenced state. In contrast, selected single copy genes displayed no change in histone acetylation levels, and their transcriptional rate was indistinguishable compared to Lsh-deficient cells and wild-type controls. Microarray analysis of total RNA derived from brain and liver tissues revealed that <0.4% of the 15 247 examined loci were abnormally expressed in Lsh-/-embryos and almost two-thirds of these deregulated sequences contained repeats, mainly retroviral LTR (long terminal repeat) elements. Chromatin immunoprecipitation analysis demonstrated a direct interaction of Lsh with repetitive sites in the genome. These data suggest that the repetitive sites are direct targets of Lsh action and that Lsh plays an important role as 'epigenetic guardian' of the genome to protect against deregulation of parasitic retroviral elements.

Modification of Integration Site Preferences of an HIV-1-Based Vector by Expression of a Novel Synthetic Protein

“…The difference between TIHPLE and combined control cells is statistically significant ( p ¼ 0.000; Table 2). LTR elements were reported to be associated with heterochromatin (Huang et al, 2004). The high frequency of integration into the LTR elements of TIHPLE-expressing cells is thus consistent with the hypothesis that TIHPLE diverts integration of the HIV-1-based vector into heterochromatin.…”

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].…”

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

“…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).…”