A non-enzymatic function associated with a putative histone demethylase licenses epigenetic inheritance

Abstract

H3K9 methylation (H3K9me) specifies the establishment and maintenance of transcriptionally silent epigenetic states or heterochromatin. The enzymatic erasure of histone modifications is widely assumed to be the primary mechanism that reverses epigenetic silencing. Here, we reveal an inversion of this paradigm where a putative histone demethylase Epe1 in fission yeast, has a non-enzymatic function that opposes heterochromatin assembly. An auto-inhibitory conformation regulates the non-enzymatic properties of Epe1 and licenses its interaction with Swi6 HP1 . Mutations that map to the putative catalytic JmjC domain preserve Epe1 in an auto-inhibited state which disrupts its localization to sites of heterochromatin formation and interaction with Swi6 HP1 . H3K9me relieves Epe1 from auto-inhibition and stimulates its ability to form an inhibitory complex with Swi6 HP1 in vitro and in cells. Our work reveals that histone modifications, rather than being passive scaffolds, actively participate in regulating the assembly of specific epigenetic complexes in cells.