Controlling the Controllers: Regulation of Histone Methylation by Phosphosignalling

Histone methylation is central to the regulation of eukaryotic transcription. Here, we review how the histone methylation system itself is regulated. There is substantial evidence that mammalian histone methyltransferases and demethylases are phosphorylated and regulated by upstream signalling pathways. Functional studies of specific phosphosites are revealing which kinases and pathways signal to the histone methylation system and are discovering the diverse effects of phosphorylation on enzyme function. Nevertheless, the majority of phosphosites have no known kinase or function and our understanding of how histone methylation is regulated is fragmentary. Improved approaches are needed to establish and study the key regulatory phosphorylation sites on histone methyltransferases and demethylases, to avoid focus on constitutive sites which may have little regulatory purpose.