Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation

Abstract

Cytosine methylation of mammalian DNA is essential for the proper epigenetic regulation of gene expression and maintenance of genomic integrity. To define the mechanism through which demethylated cells die, and to establish a paradigm for identifying genes regulated by DNA methylation, we have generated mice with a conditional allele for the maintenance DNA methyltransferase gene Dnmt1. Cre-mediated deletion of Dnmt1 causes demethylation of cultured fibroblasts and a uniform p53-dependent cell death. Mutational inactivation of Trp53 partially rescues the demethylated fibroblasts for up to five population doublings in culture. Oligonucleotide microarray analysis showed that up to 10% of genes are aberrantly expressed in demethylated fibroblasts. Our results demonstrate that loss of Dnmt1 causes cell-type-specific changes in gene expression that impinge on several pathways, including expression of imprinted genes, cell-cycle control, growth factor/receptor signal transduction and mobilization of retroelements.

Alternative splicing and expression analysis of bovine DNA methyltransferase 1

“…More specifically, the enzyme has been implicated in the maintenance of bulk DNA methylation in adult cells and the maintenance of imprinting in 8-cell stage embryos (Li et al, 1992;Howell et al 2001). Deletion of Dnmt1 in adult cells such as fetal fibroblasts induces apoptosis and deregulation of transcription (Jackson-Grusby et al, 2001).…”

Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice

“…Our findings validate the proposed role of DNA methylation in suppression of transposable elements in mammalian cells and demonstrate the importance of DNA methylation for normal cell function as well as the potential consequences of spontaneously occurring or chemically induced DNA hypomethylation. Oncogene (2008) 27, 404-408; doi:10.1038/sj.onc.1210631; published online 9 July 2007 Keywords: DNA hypomethylation; transposable elements; Notch1; T-cell lymphoma Proper methylation of genomic DNA is essential for normal development and for survival of somatic cells (Li et al, 1992;Jackson-Grusby et al, 2001). Human tumors display abnormal methylation patterns including genomewide hypomethylation and site-specific hypermethylation (Ehrlich, 2002;Jones and Baylin, 2002).…”

A new perspective on neural tube defects: Folic acid and microRNA misexpression

“…Dnmt1 is important for remethylation of the genome in early embryogenesis, with Dnmt1 2/2 mutants usually dying by E8.0 (Biniszkiewicz et al, 2002;Jackson et al, 2004;Jackson-Grusby et al, 2001). Dnmt1 is a predicted target of miR-221 in both humans and mice by both databases, as well as a predicted target for miR-222 by both the databases for mice and by miRBase for humans.…”

“…In mammalian embryonic development, prior to implantation, the genome becomes demethylated by the 8-to 16-cell stage, with the inner cell mass undergoing global remethylation at discrete CpG sites before onset of gastrulation (Finnell et al, 2002;Kafri et al, 1992;Santos et al, 2002). This is then followed by the demethylation and transcription of tissue-specific genes during organogenesis (Jackson-Grusby et al, 2001). Studies have shown that improper methylation patterns can lead to multiple developmental malformations and embryonic lethality.…”

“…Misexpression of b-catenin has been shown to increase cellular proliferation and delay differentiation in the brain, increasing the number of NPCs, as well as the number of neurons (Hatakeyama et al, 2004). Despite a potential increase in SAH hydrolase (and thus a decrease in SAH), downregulation of Dnmt1 by misexpression of miR-221 and miR-222 seems a good candidate for investigation as Dnmt1 is highly expressed in the developing CNS (Fan et al, 2001), its overexpression has been shown to decrease differentiation, and may increase proliferation via an increase in b-catenin (Jackson et al, 2004;Jackson-Grusby et al, 2001).…”