An epigenetic switch ensures transposon repression upon dynamic loss of DNA methylation in embryonic stem cells

Abstract

DNA methylation is extensively remodeled during mammalian gametogenesis and embryogenesis. Most transposons become hypomethylated, raising the question of their regulation in the absence of DNA methylation. To reproduce a rapid and extensive demethylation, we subjected mouse ES cells to chemically defined hypomethylating culture conditions. Surprisingly, we observed two phases of transposon regulation. After an initial burst of de-repression, various transposon families were efficiently re-silenced. This was accompanied by a reconfiguration of the repressive chromatin landscape: while H3K9me3 was stable, H3K9me2 globally disappeared and H3K27me3 accumulated at transposons. Interestingly, we observed that H3K9me3 and H3K27me3 occupy different transposon families or different territories within the same family, defining three functional categories of adaptive chromatin responses to DNA methylation loss. Our work highlights that H3K9me3 and, most importantly, polycomb-mediated H3K27me3 chromatin pathways can secure the control of a large spectrum of transposons in periods of intense DNA methylation change, ensuring longstanding genome stability.DOI: http://dx.doi.org/10.7554/eLife.11418.001

An RB-EZH2 Complex Mediates Silencing of Repetitive DNA Sequences

“…Repetitive sequences in ESCs are enriched for H3K9me2/3, H4K20me3, and H3K27me3 (Day et al, 2010). Upon loss of DNA methylation, H3K27me3 expands to maintain silencing of interspersed and tandem repeat sequences (Walter et al, 2016). Following genetic ablation of H3K9 histone methyl transferases, H3K27me3 compensates for H3K9me3 loss at interspersed and pericentromeric repeats (Peters et al, 2003).…”

“…Following genetic ablation of H3K9 histone methyl transferases, H3K27me3 compensates for H3K9me3 loss at interspersed and pericentromeric repeats (Peters et al, 2003). However, additional deletion of the Polycomb repressor complex 2 (PRC2) subunit EED can deregulate these repetitive sequences, indicating redundancy of repressive mechanisms (Walter et al, 2016). Proteomic analysis of ESCs indicates that 60% of histone H3 proteins are composed of H3K27me2/3 modifications (Peters et al, 2003).…”

DNA (De)Methylation: The Passive Route to Naïvety?

“…Another direct target of Prdm14 is Glp, an important co-factor for the histone methyltransferase G9a [13,15], which is known to deposit H3K9me2 modification. Previously reported upregulation of Prdm14 in 2i conditions [3,4] may thus lead to observed lower Glp [3] and hence lower H3K9me2 [3,9,10] Glp repressed by Prdm14…”

“…As H3K9me2 is globally reduced in 2i conditions [3,9,10], it is possible that this may affect Uhrf1 recruitment. In keeping with this, the authors show a small yet significant increase in DNA methylation at regions where H3K9me2 is present in 2i.…”

“…In addition, a role for the Tet enzymes that convert 5mC to 5hmC has also been proposed as an alternative or complimentary mechanism [5,8]. Culture in 2i also leads to a redistribution of, amongst others, the repressive histone modification H3K27me3 [2] and a decrease in H3K9me2 [3,9]. Last but not least, changes in the expression of many epigenetic modifiers accompany alterations in epigenetic modifications, which suggests that ES cells cultured in 2i represent a distinct yet interchangeable epigenetic state [3].…”