March 05, 2022
The “language” of histone methylation has been a subject of intensive study due to numerous diseases and disorders linked to faulty methylation patterns. Methylation patterns are “written” by enzymes in response to signals and then “read” by effector proteins recognizing methyl residues on highly specific lysine residues, leading to either large- or small-scale alterations in the transcriptional state of chromatin. In response to the cellular environment, signals are sent for the opposing processes of “writing” and “erasing” methylation. Conserved methyltransferase enzymes are the “writers” and demethylase enzymes are the “erasers,” with the activity of each regulated by cellular signals in ways that are poorly understood.
Whereas humans have 35 writers and 23 erasers, yeast has only four of each. Given orthology within each class of writers and erasers (as defined by the particular lysines methylated or demethylated), this makes yeast a perfect model system for digging into the links that connect cellular signals to specific methylation patterns on chromatin.
In a recent study in the Journal of Molecular Biology, Separovich et al. describe a systematic phosphosite mutant library that allowed the identification of key phosphorylated residues transducing cellular signals onto a writer/eraser pair. In response to environmental stress, Set2p methylates lysine 36 on histone H3 while Jhd1p opposes this action by demethylation. Using AlphaFold, they modeled the relationship between the specific phosphorylated residues and showed the key regulator of methylation activity (T127 on Set2p) is spatially proximal to the target lysine residue in the histone.
Upon analysis of differential expression for the sets of phosphonull and phosphomimetic mutants, they showed the proteins most affected by histone methylation clustered into GO categories consistent with cellular response to stress, e.g. ion membrane transport, lipid biosynthesis, ergosterol biosynthesis, and protein mannosylation.
While the kinase(s) responsible for phosphorylating the writer/eraser pair have yet to be identified, there are good candidates to test in yeast. The identification of the yeast players in signal transduction from environment to chromatin will undoubtedly be of use to those studying the much more complex system in humans.
Categories: Research Spotlight