Functional mammalian homologues of the Drosophila PEV-modifier Su(var)3-9 encode centromere-associated proteins which complex with the heterochromatin component M31

The chrome and SET domains are conserved sequence moths present in chromoso mal proteins that function in epigenetic control of gene expression, presum ably by modulating higher order chromatin, Based on sequence information fr om the SET domain, we have isolated human (SUV39H1) and mouse (Suv39h1) hom ologues of the dominant Drosophila modifier of position-effect-variegation (PEV) Su(var)3-9. Mammalian homologues contain, in addition to the SET doma in, the characteristic chrome domain, a combination that is also preserved in the Schizosaccharyomyces pombe silencing factor clr4. Chromatin-dependen t gene regulation is demonstrated by the potential of human SUV39H1 to incr ease repression of the pericentromeric white marker gene in transgenic flie s. Immunodetection of endogenous Suv39h1/SUV39H1 proteins in a variety of m ammalian cell lines reveals enriched distribution at heterochromatic foci d uring interphase and centromere-specific localization during metaphase, In addition, Suv39h1/SUV39H1 proteins associate with M31, currently the only o ther characterized mammalian SU(VAR) homologue, These data indicate the exi stence of a mammalian SU(VAR) complex and define Suv39h1/SUV39H1 as novel c omponents of mammalian higher order chromatin.