Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain

Heterochromatin protein 1 (HP1) is localized at heterochromatin sites where it mediates gene silencing(1,2). The chromo domain of HP1 is necessary for both targeting and transcriptional repression(3,4). In the fission yeast S chizosaccharomyces pombe, the correct localization of Swi6 (the HP1 equival ent) depends on Clr4, a homologue of the mammalian SUV39H1 histone methylas e(5,6). Both Clr4 and SUV39H1 methylate specifically lysine 9 of histone H3 (ref. 6). Here we show that HP1 can bind with high affinity to histone H3 methylated at lysine 9 but not at lysine 4. The chromo domain of HP1 is ide ntified as its methyl-lysine-binding domain. A point mutation in the chromo domain, which destroys the gene silencing activity of HP1 in Drosophila(3) , abolishes methyl-lysine-binding activity. Genetic and biochemical analysi s in S. pombe shows that the methylase activity of Clr4 is necessary for th e correct localization of Swi6 at centromeric heterochromatin and for gene silencing. These results provide a stepwise model for the formation of a tr anscriptionally silent heterochromatin: SUV39H1 places a 'methyl marker' on histone H3, which is then recognized by HP1 through its chromo domain. Thi s model may also explain the stable inheritance of the heterochromatic stat e.