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Histone H3 lysine 36 methylation (H3K36me) is thought to participate in a host of co-transcriptional regulatory events. To study the function of this residue independent from the enzymes that modify it, we used a ‘histone replacement’ system in Drosophila to generate a non-modifiable H3K36 lysine-to-arginine (H3K36R) mutant. We observed global dysregulation of mRNA levels in H3K36R animals that correlates with the incidence of H3K36me3. Similar to previous studies, we found that mutation of H3K36 also resulted in H4 hyperacetylation. However, neither cryptic transcription initiation, nor alternative pre-mRNA splicing, contributed to the observed changes in expression, in contrast with previously reported roles for H3K36me. Interestingly, knockdown of the RNA surveillance nuclease, Xrn1, and members of the CCR4-Not deadenylase complex, restored mRNA levels for a class of downregulated, H3K36me3-rich genes. We propose a post-transcriptional role for modification of replication-dependent H3K36 in the control of metazoan gene expression. DOI: http://dx.doi.org/10.7554/eLife.23249.001, eLife digest In a single human cell there is enough DNA to stretch over a meter if laid end to end. To fit this DNA inside the cell – which is less than 20 micrometers in diameter – the DNA is tightly wrapped around millions of proteins known as histones, which look like “beads” along a “string” of DNA. These histones can prevent other proteins from binding to DNA and activating specific genes. Therefore, cells use enzymes to chemically modify histones to allow particular stretches of DNA to be unwrapped at specific times. Proteins are made up of building blocks called amino acids. A specific amino acid on histones known as H3K36 is modified in certain sections of DNA that suggest it affects the activities of many genes. However, the precise role of this amino acid remains unclear. Previous studies have tried to investigate this by removing the enzymes that modify it, but these enzymes can also modify many other proteins, making it difficult to know what exactly causes the changes in gene activity. Fruit flies are often used in experiments as models of how genetic processes work in humans and other animals. Like us, fruit flies also package their DNA using histones. To investigate the role of H3K36, Meers et al. generated a mutant fruit fly that has a version of the amino acid that cannot be chemically modified by the normal enzymes. Unexpectedly, the experiments suggest that some changes in gene activity that have been previously reported to be caused by modifying H3K36 might actually be due to other factors. Meers et al. found that H3K36 modifications may instead “mark” certain genes to be more active than they otherwise would be. These findings provide a starting point for understanding exactly how H3K36 regulates gene activity. The next challenge is to refine our understanding of how H3K36 modification affects genes in cancer and other diseases, which may aid the development of new therapies to treat these conditions. DOI: http://dx.doi.org/10.7554/eLife.23249.002

The epigenetic inheritance of DNA methylation requires UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that recruits DNMT1 to sites of newly replicated DNA through ubiquitylation of histone H3. UHRF1 binds DNA with selectivity towards hemi-methylated CpGs (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive. Here, we reveal that the interaction of UHRF1 with HeDNA is required for DNA methylation but is dispensable for chromatin interaction, which is governed by reciprocal positive cooperativity between the UHRF1 histone- and DNA-binding domains. HeDNA recognition activates UHRF1 ubiquitylation towards multiple lysines on the H3 tail adjacent to the UHRF1 histone-binding site. Collectively, our studies are the first demonstrations of a DNA-protein interaction and an epigenetic modification directly regulating E3 ubiquitin ligase activity. They also define an orchestrated epigenetic control mechanism involving modifications both to histones and DNA that facilitate UHRF1 chromatin targeting, H3 ubiquitylation, and DNA methylation inheritance. DOI: http://dx.doi.org/10.7554/eLife.17101.001, eLife digest Cells are able to regulate the activity of their genes in response to different cues. Genetic information is encoded in DNA and one way to regulate gene activity is to modify the DNA by attaching chemical “epigenetic” markers to it. When a cell divides, these epigenetic markers can be inherited by the daughter cells so that they share the same patterns of gene activity as the parent cell. When the DNA of the parent cell is copied prior to cell division, the epigenetic markers are also copied onto the new DNA. Mistakes in this process are linked to a wide range of diseases in humans, such as cancer and neurological disorders. One type of epigenetic marker is known as a methyl tag and it is added to DNA by certain enzymes in a process called DNA methylation. A protein called UHRF1 is required for human cells to inherit patterns of DNA methylation through cell division. This protein binds to newly copied DNA that lacks some methyl tags as well as to another protein associated with DNA called histone H3. UHRF1 modifies histone H3 by attaching a small protein molecule called ubiquitin to it. This helps to recruit a DNA methylation enzyme to place methyl tags on the newly copied DNA. However, it was not clear how the various properties of UHRF1 allow it to control how DNA methylation is inherited. Harrison et al. addressed this question by studying purified proteins and DNA fragments outside of living cells. The results show that UHRF1 binding to DNA and histone H3 work together to bring UHRF1 to the sites on DNA that require methylation. Further experiments revealed that the methylation pattern on newly copied DNA is able to activate the ability of UHRF1 to place ubiquitin on histone H3. The findings of Harrison et al. reveal a new mechanism by which dividing cells control how DNA methylation is inherited by their daughter cells. A future challenge will be to find out how attaching ubiquitin to histone H3 activates DNA methylation. DOI: http://dx.doi.org/10.7554/eLife.17101.002