In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse

Abstract

Methylation of cytosines (5meC) is a widespread heritable DNA modification. During mammalian development, two global demethylation events are followed by waves of de novo DNA methylation. In vivo mechanisms of DNA methylation establishment are largely uncharacterized. Here, we use Saccharomyces cerevisiae as a system lacking DNA methylation to define the chromatin features influencing the activity of the murine DNMT3B. Our data demonstrate that DNMT3B and H3K4 methylation are mutually exclusive and that DNMT3B is co-localized with H3K36 methylated regions. In support of this observation, DNA methylation analysis in yeast strains without Set1 and Set2 shows an increase of relative 5meC levels at the transcription start site and a decrease in the gene-body, respectively. We extend our observation to the murine male germline, where H3K4me3 is strongly anti-correlated while H3K36me3 correlates with accelerated DNA methylation. These results show the importance of H3K36 methylation for gene-body DNA methylation in vivo.DOI: http://dx.doi.org/10.7554/eLife.06205.001

Switching between Epigenetic States at Pericentromeric Heterochromatin

“…The mechanism of DNMT3 targeting to PHC remains unclear, but might involve recognition of other residues in the H3 tail. Specific domains in DNMT3A and -3B and in DNMT3L (PWWP and ADD domains, respectively, named after a conserved Proline-Tryptophan-Tryptophan-Proline motif, and after a domain found in ATRX, DNMT3 and DNMT3L proteins) show significant affinity for H3K36me3 and for the unmodified N-terminal tail of histone H3, in particular for the unmodified state of the lysine 4, respectively [31,32]. As PHC does not harbor significant modifications on H3K4, this unmodified configuration might be sufficient to attract DNMT3 to PHC in the absence of HP1, when SUV39H1/2 are absent.…”

Epigenetic Control of Stem Cell Potential during Homeostasis, Aging, and Disease

“…In contrast to the largely antagonistic relationship of H3K27 and H3K4 methylation with DNA methylation, H3K36me3, a hallmark of transcriptional elongation, appears to directly recruit and interact with de novo DNA methyltransferases (Dhayalan et al, 2010, Morselli et al, 2015). Consistent with this hypothesis, regions in which H3K36me3 decreased in aged HSCs also displayed DNA hypo-methylation (Sun et al, 2014).…”

Epigenetic factors in the regulation of prospermatogonia and spermatogonial stem cells

“…Global DNA methylation levels rise from w10% in E13.5 PGCs to w50% in E16.5 prospermatogonia, coinciding with redistributing the active marks of H3K4me2/3 and H3K36me3 in prospermatogonia (Singh et al 2013, Morselli et al 2015. The elevated expression of DNA methyltransferase 3A/3B/3L (DNMT3s) during these stages suggests the potential contribution of de novo DNA methylation at this stage (La Salle et al 2004, Sakai et al 2004.…”

“…Methylated H3K4 protects the underlying DNA sequence from de novo DNA methylation at gene promoter regions, as methylated H3K4 inhibit the interaction between the H3 histone tail and the ADD domain of DNMT3s , Ooi et al 2007, Zhang et al 2010, Singh et al 2013. On the other hand, H3K36me3 is positively correlated with de novo methylation within gene bodies to promote transcriptional elongation in fetal and neonatal prospermatogonia (Morselli et al 2015). Interestingly, DNA methylation is found more frequently in regions of low CpG density than in regions with high CpG density (Kobayashi et al 2013).…”