Sequence of centromere separation: effect of 5-azacytidine-induced epigenetic alteration

The factors which control the sequential separation of the various chromoso mes in a genome at the meta-anaphase junction are not well understood. In g enomes in which separation is correlated with the quantity of pericentric h eterochromatin one factor appears to be the epigenetic nature, namely conde nsation, of pericentric heterochromatin, When we induced decondensation of pericentric heterochromatin in mouse cells with 10(-6), 4 x 10(-6) and 6 x 10(-6) M 5-azacytidine (5-AC) for 8 h, it resulted in alteration of the seq uence of centromere separation. The centromeres which lacked pericentric he terochromatin appeared not to have been affected because there could not be an epigenetic alteration induced by 5-AC, The major effect was on chromoso mes with the largest quantity of pericentric heterochromatin. These chromos omes separated at significantly higher frequency than in the untreated popu lation. We also treated human cells, in which separation does not depend up on the quantity of heterochromatin, with 2 x 10(5) and 6 x 10(-6) M S-AC fo r 5 and 8 h, Compared with the control, 5-AC treatment resulted in an incre ased frequency of separated centromeres of acrocentric chromosomes in relat ion to those of nonacrocentric chromosomes. In the control the acrocentric chromosomes are the last to separate; in the treated population there was a lmost random separation of the two types of chromosomes. This epigenetic al teration might be another factor which results in genesis of aneuploidy.