Global hypomethylation of the genome in XX embryonic stem cells

Abstract

Embryonic stem (ES) cells are important tools in the study of gene function and may also become important in cell therapy applications. Establishment of stable XX ES cell lines from mouse blastocysts is relatively problematic owing to frequent loss of one of the two X chromosomes. Here we show that DNA methylation is globally reduced in XX ES cell lines and that this is attributable to the presence of two active X chromosomes. Hypomethylation affects both repetitive and unique sequences, the latter including differentially methylated regions that regulate expression of parentally imprinted genes. Methylation of differentially methylated regions can be restored coincident with elimination of an X chromosome in early-passage parthenogenetic ES cells, suggesting that selection against loss of methylation may provide the basis for X-chromosome instability. Finally, we show that hypomethylation is associated with reduced levels of the de novo DNA methyltransferases Dnmt3a and Dnmt3b and that ectopic expression of these factors restores global methylation levels.

Biological differences between in vitro produced bovine embryos and parthenotes

“…DNMT3A sets up the methyl-CG landscape of the genome early in the development. The reduced DNMT3A levels found in our study suggest a lower methylation activity in parthenotes, which agrees with a low expression of DNMT3A reported in female blastocysts (Bermejo-Alvarez et al 2008) and XX ES cell lines as it compares with XY or XO lines (Zvetkova et al 2005). Sagirkaya et al (2006) found that the DNMT3A expression associates with a lower rate of blastocyst development.…”

Diverse Epigenetic Profile of Novel Human Embryonic Stem Cell Lines

“…Although the DPPA3 and DPPA5 genes are located on autosomes, we cannot rule out the possibility that methylation pattern could be connected with early sex determination events or represents fine differences between male and female lines due to both the X and Y chromosome gene transcription. 33 It is also supported by recent finding of Zvetkova et al 34 where authors have demonstrated hypomethylation of mouse genome in XX embryonic stem cells. Our findings may explain the differences in gene expression profile of different hESC lines, and underlines the importance of studying the epigenetic profile of each hESC line.…”

Primordial Germ Cells in Mice

“…Genomewide methylation analyses of CpG dinucleotide sequences have revealed a significant hypomethylation of both male and female PGCs at E13.5 (Popp et al 2010;Guibert et al 2012). One study shows that the female PGCs bear a lower methylation level than the male PGCs (Popp et al 2010), which may be an effect of their having two active X chromosomes because of their X-reactivation (Zvetkova et al 2005). In PGCs, long terminal repeat (LTR) retrotransposon sequences such as intracisternal A particles (IAPs) are more resistant to demethylation, whereas genic, intergenic, and other transposon sequences are apparently globally demethylated (Popp et al 2010;Guibert et al 2012).…”