Aberrant DNA methylation in ES cells.

Both mouse and human embryonic stem cells can be differentiated in vitro to produce a variety of somatic cell types. Using a new developmental tracing approach, we show that these cells are subject to massive aberrant CpG island de novo methylation that is exacerbated by differentiation in vitro. Bioinformatics analysis indicates that there are two distinct forms of abnormal de novo methylation, global as opposed to targeted, and in each case the resulting pattern is determined by molecular rules correlated with local pre-existing histone modification profiles. Since much of the abnormal methylation generated in vitro appears to be stably maintained, this modification may inhibit normal differentiation and could predispose to cancer if cells are used for replacement therapy. Excess CpG island methylation is also observed in normal placenta, suggesting that this process may be governed by an inherent program.

Integrative analysis of methylome and transcriptome reveals the importance of unmethylated CpGs in non-CpG island gene activation.

BACKGROUND: Promoter methylation is associated with gene repression; however, little is known about its mechanism. It was proposed that the repression of methylated genes is achieved through the recruitment of methyl binding proteins (MBPs) that participate in closing the chromatin. An alternative mechanism suggests that methylation interferes with the binding of either site specific activators or more general activators that bind to the CpG dinucleotide. However, the relative contribution of these two mechanisms to gene repression is not known. RESULTS: Bioinformatics analyses of genome-wide transcriptome and methylome data support the latter hypothesis by demonstrating a strong association between transcription and the number of unmethylated CpGs at the promoter of genes lacking CpG islands. CONCLUSIONS: Our results suggest that methylation represses gene expression mainly by preventing the binding of CpG binding activators.