Antagonism between DNA and H3K27 Methylation at the Imprinted Rasgrf1 Locus

Abstract

At the imprinted Rasgrf1 locus in mouse, a cis-acting sequence controls DNA methylation at a differentially methylated domain (DMD). While characterizing epigenetic marks over the DMD, we observed that DNA and H3K27 trimethylation are mutually exclusive, with DNA and H3K27 methylation limited to the paternal and maternal sequences, respectively. The mutual exclusion arises because one mark prevents placement of the other. We demonstrated this in five ways: using 5-azacytidine treatments and mutations at the endogenous locus that disrupt DNA methylation; using a transgenic model in which the maternal DMD inappropriately acquired DNA methylation; and by analyzing materials from cells and embryos lacking SUZ12 and YY1. SUZ12 is part of the PRC2 complex, which is needed for placing H3K27me3, and YY1 recruits PRC2 to sites of action. Results from each experimental system consistently demonstrated antagonism between H3K27me3 and DNA methylation. When DNA methylation was lost, H3K27me3 encroached into sites where it had not been before; inappropriate acquisition of DNA methylation excluded normal placement of H3K27me3, and loss of factors needed for H3K27 methylation enabled DNA methylation to appear where it had been excluded. These data reveal the previously unknown antagonism between H3K27 and DNA methylation and identify a means by which epigenetic states may change during disease and development.

Genome-Wide and Organ-Specific Landscapes of Epigenetic Modifications and Their Relationships to mRNA and Small RNA Transcriptomes in Maize

“…Interestingly, we found that while multiple activating epigenetic marks tended to occur together, the two repressive marks under study, H3K27me3 and DNA methylation, were more likely to exclude each other at the same loci ( Figures 4D and 4E). This supports similar findings for genome-wide studies in Arabidopsis (Mathieu et al, 2005;Zhang et al, 2007) and for a locus-specific analysis in mouse (Lindroth et al, 2008). For example, in Arabidopsis, <10% of H3K27me3-covered regions overlapped with DNA methylation (Zhang et al, 2007).…”

Dynamic stage-specific changes in imprinted differentially methylated regions during early mammalian development and prevalence of non-CpG methylation in oocytes

“…3). This is consistent with previous, but more limited, reports that the unmethylated H19 promoter in sperm becomes methylated later in embryos (Ferguson-Smith et al, 1993), and that an unmethylated region is present at the Rasgrf1 locus in sperm (Lindroth et al, 2008). Both fused DMRs, and also the paternally methylated Dlk1-Gtl2 (also known as Meg3) DMR, were contracted substantially in 12.5 dpc embryos by regressions at both ends.…”

Loss of HP1 causes depletion of H3K27me3 from facultative heterochromatin and gain of H3K27me2 at constitutive heterochromatin

“…While recent observations in both plant and animal systems revealed that removal of DNA methylation can profoundly influence the distribution of H3K27me3 (Mathieu et al 2005;Lindroth et al 2008;Wu et al 2010;Deleris et al 2012;Hagarman et al 2013;Reddington et al 2013), the fact that DNA methylation can indirectly induce H3K9 methylation in plants (Tariq and Paszkowski 2004) and animals (Jin et al 2011) raised the possibility that some, or all, of the observed effects were indirect. We therefore tested for possible effects of knocking out either the single N. crassa H3K9me3 methyltransferase dim-5 (Tamaru and Selker 2001;Tamaru et al 2003) or the single N. crassa DNA methyltransferase gene dim-2 (Kouzminova and Selker 2001).…”

“…In early studies with mouse embryonic stem cells, reduced DNA methylation resulting from mutation of either the maintenance methyltransferase gene dnmt1 or the de novo DNA methyltransferase genes dmnt3a and dnmt3b did not result in an obvious change in the distribution of H3K27me (Martens et al 2005). However, subsequent studies with Arabidopsis (Mathieu et al 2005;Deleris et al 2012), mouse embryonic fibroblasts (Lindroth et al 2008;Reddington et al 2013), embryonic stem cells (Hagarman et al 2013), and neural stem cells (Wu et al 2010) revealed that loss of DNA methylation, caused by disruption of DNA methyltransferase genes or treatment with the demethylating agent 5-azacytidine, provided the most potent trigger of H3K27me3 redistribution.…”