The organization of chromatin into higher-order structures influences chromosome 
function and epigenetic gene regulation. Higher-order chromatin has been 
proposed to be nucleated by the covalent modification of histone tails and the 
subsequent establishment of chromosomal subdomains by non-histone modifier 
factors. Here we show that human SUV39H1 and murine Suv39h1--mammalian 
homologues of Drosophila Su(var)3-9 and of Schizosaccharomyces pombe 
clr4--encode histone H3-specific methyltransferases that selectively methylate 
lysine 9 of the amino terminus of histone H3 in vitro. We mapped the catalytic 
motif to the evolutionarily conserved SET domain, which requires adjacent 
cysteine-rich regions to confer histone methyltransferase activity. Methylation 
of lysine 9 interferes with phosphorylation of serine 10, but is also influenced 
by pre-existing modifications in the amino terminus of H3. In vivo, deregulated 
SUV39H1 or disrupted Suv39h activity modulate H3 serine 10 phosphorylation in 
native chromatin and induce aberrant mitotic divisions. Our data reveal a 
functional interdependence of site-specific H3 tail modifications and suggest a 
dynamic mechanism for the regulation of higher-order chromatin.