Regulation of chromatin structure by site-specific histone H3 methyltransferases

The organization of chromatin into higher-order structures influences chrom osome function and epigenetic gene regulation. Higher-order chromatin has b een proposed to be nucleated by the covalent modification of histone tails and the subsequent establishment of chromosomal subdomains by non-histone m odifier factors. Here we show that human SUV39H1 and murine Suv39h1-mammali an homologues of Drosophila Su(var)3-9 and of Schizosaccharomyces pombe cir 4-encode histone H3-specific methyltransferases that selectively methylate lysine 9 of the amino terminus of histone H3 in vitro. We mapped the cataly tic motif to the evolutionarily conserved SET domain, which requires adjace nt cysteine-rich regions to confer histone methyltransferase activity. Meth ylation of lysine 9 interferes with phosphorylation of serine 10, but is al so influenced by preexisting modifications in the amino terminus of H3. In vivo, deregulated SUV39H1 or disrupted Suv39h activity modulate H3 serine 1 0 phosphorylation in native chromatin and induce aberrant mitotic divisions . Our data reveal a functional interdependence of site-specific H3 tail mod ifications and suggest a dynamic mechanism for the regulation of higher-ord er chromatin.