Monomethylated H3K27 is more than just an intermediate.
We often talk about biological traits as if they’re written in our DNA, but some of them aren’t in our DNA at all—instead, they’re on it in the form of chemical tags on the histone proteins our genomic DNA is wrapped around. During development, each cell’s genome is indexed with these tags, which help determine whether a stretch of DNA should be actively transcribed or silent. In a new study published in GENETICS, Wang et al. investigated how the marks left by one of the most important players in this system are interpreted.
PRC2 is a complex of proteins that turns off genes by flagging histones around the genes with methyl groups. One at a time, PRC2 adds these groups to a specific lysine residue (K27) of histone H3 through a process called methylation. Specifically, trimethylation of H3K27 is required for silencing; if there are any fewer than three methyl groups, the gene won’t be turned off.
DNA silenced in this way is relatively rare, with trimethylated H3K27 only being found at around 100 sites in the genome. In contrast, genomic regions littered with mono- and dimethylated H3K27 are more common. Wang et al. wondered whether these mono- and dimethylated H3K27 were simply intermediates left behind by PRC2 or had their own purposes.
To test for function of H3K27 monomethylation, the group engineered a version of PRC2 that was adept at adding one methyl group but very inefficient at adding more. They found that, in a fruit fly cell line, this version of PRC2 led to increased expression of genes that PRC2 normally targets for silencing. However, this wasn’t enough to show that monomethylation has a specific function, since silencing is known to require trimethylation of H3K27.
The real insight came from comparing this result to what happened when they ran the same experiment using a version of PRC2 that’s inefficient at adding any number of methyl groups. Cells with this defective PRC2 had lower expression of PRC2-target genes than cells with the monomethylating PRC2 did, indicating that having a single methyl group on H3K27 may specifically increase gene expression above baseline.
This study adds to a growing collection of work on the importance of the number of methyl groups added to histones. Monomethylation on a different lysine residue (K9) of the histone H3 is associated with active genes, whereas di- or trimethylation usually indicates gene repression. If different numbers of methyl groups lead to multiple, distinct states, this could be exploited in drug design. Many cancers are associated with faulty gene regulation, so a targeted drug that precisely tuned the number of methyl groups on histones could help restore order by rewriting the genome’s index.
A Role for Monomethylation of Histone H3-K27 in Gene Activity in Drosophila
Liangjun Wang, Preeti Joshi, Ellen L. Miller, LeeAnn Higgins, Matthew Slattery and Jeffrey A. Simon
Genetics 2018 208: 1023–1036; https://doi.org/10.1534/genetics.117.300585