SRP105341 PRJNA384583 GSE98282 ChIP Seq analysis of H3K4me3 and H3K79me3 in euploid and aneuploid Saccharomyces cerevisiae Aneuploidy and epigenetic alterations have long been associated with carcinogenesis, but it was unknown whether aneuploidy could disrupt the epigenetic states required for cellular differentiation. In this study, we found that ~3% of random aneuploid karyotypes in yeast disrupt the stable inheritance of silenced chromatin during cell proliferation. Karyotype analysis revealed that this phenotype was significantly correlated with gains of chromosomes III and X. Chromosome X disomy alone was sufficient to disrupt chromatin silencing and yeast mating-type identity as indicated by a lack of growth response to pheromone. The silencing defect was not limited to the cryptic mating type loci but was associated with global changes in histone modifications and chromatin localization of Sir2 histone deacetylase. The chromatin-silencing defect of disome X can be partially recapitulated by increasing the copy number of several genes on chromosome X. These results suggest that aneuploidy can directly cause epigenetic instability and disrupt cellular differentiation. Overall design: WT haploid and disome X yeast strains were grown in YPD to mid-log phase and harvested for genome-wide ChIP studies of histone modifications H3K4me3 and H3K79me3 in duplicate. GSE98282