Lsh is involved in de novo methylation of DNA

Abstract

Deletion of Lsh perturbs DNA methylation patterns in mice yet it is unknown whether Lsh plays a direct role in the methylation process. Two types of methylation pathways have been distinguished: maintenance methylation by Dnmt1 occurring at the replication fork, and de novo methylation established by the methyltransferases Dnmt3a and Dnmt3b. Using an episomal vector in LshÀ/À embryonic fibroblasts, we demonstrate that the acquisition of DNA methylation depends on the presence of Lsh. In contrast, maintenance of previously methylated episomes does not require Lsh, implying a functional role for Lsh in the establishment of novel methylation patterns. Lsh affects Dnmt3a as well as Dnmt3b directed methylation suggesting that Lsh can cooperate with both enzymatic activities. Furthermore, we demonstrate that embryonic stem cells with reduced Lsh protein levels show a decreased ability to silence retroviral vector or to methylate endogenous genes. Finally, we demonstrate that Lsh associates with Dnmt3a or Dnmt3b but not with Dnmt1 in embryonic cells. These results suggest that the epigenetic regulator, Lsh, is directly involved in the control of de novo methylation of DNA.

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).…”

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

“…It has been also confirmed that DNMT3L aids the de novo methyltransferases by maximizing their ability to bind to DNA and stimulates their activity (Goll et al, 2006). Even though the identification of the enzymes responsible for methylation patterns are now known, the exact molecular mechanisms and important cofactors that aid efficient enzymatic activity to the right sites, remain poorly understood (Zhu et al, 2006).…”

“…Consequently, maintenance methylation activity is found in all somatic cells while the maximum de novo methylation activity is found in embryonic cell lines, germ cells, or in post-implantation embryos (Zhu et al, 2006).…”

“…It is believed that aberrant methylation patterns can be implicated in tumorigenesis by causing genomic instability, abnormal imprinting, and deregulated expression of oncogenes or tumor suppressor genes (Zhu et al, 2006). It is well established that epigenetic changes play a major role in predisposing organisms to cancer/minor effects of destabilization.…”

“…Furthermore, aberrant methylation patterns are believed to be involved in tumorigenesis, causing instability, abnormal imprinting and deregulated expression of oncogenes or tumor suppressor genes (Zhu et al, 2006).…”