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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, eLife digest In animals and other multicellular organisms, there are many different types of cells that each perform particular roles in the body. This is possible because the genetic information—which is the same in all cells—is controlled so that only a subset of all the genes within an individual cell are ‘switched on’ at a particular time. Genetic information is contained within molecules of DNA, which are wrapped around proteins called histones. The genes in regions of DNA where these histones are packed tightly together tend to be switched off, while genes in regions of DNA that are loosely packed tend to be switched on. The level of packaging is controlled by the addition of ‘methyl’ tags to the histone proteins. These tags can also be added directly to the DNA in a process called DNA methylation. Enzymes called methyltransferases add the tags to the DNA, which tends to switch off the gene. The locations of the methyl tags can be copied when the DNA replicates before the cell divides so that the pattern of DNA methylation can be passed on to its daughter cells. However, it is not clear how the methyltransferases are able to target particular regions for methylation. To address this question, Morselli et al. introduced a methyltransferase called DNMT3b into yeast, a single-celled organism that does not normally add methyl tags to its DNA. The experiments show that the activity of the enzyme is affected by the presence of methyl tags on certain histone proteins. For example, a methyl tag at one particular site on a histone, called H3K4, prevents the DNMT3b enzyme from adding methyl tags to DNA. However, a methyl tag at another site called H3K36 promotes DNA methylation. Morselli et al. found that these two histone sites had similar effects on DNA methylation in mouse sperm cells. Morselli et al.'s findings may be useful in the future development of treatments for cancer and other diseases that are caused by defects in DNA methylation. DOI: http://dx.doi.org/10.7554/eLife.06205.002