Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Medicine, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
Chris W Seidel
Stowers Institute for Medical Research, Missouri, United States
Jin Zhu
Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, United States
Hung-Ji Tsai
Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, United States
Sarah E Smith
Stowers Institute for Medical Research, Missouri, United States
Pushpendra Singh
Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, United States
William D Bradford
Stowers Institute for Medical Research, Missouri, United States
Scott McCroskey
Stowers Institute for Medical Research, Missouri, United States
Anjali R Nelliat
Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, United States
Juliana Conkright
Stowers Institute for Medical Research, Missouri, United States
Allison Peak
Stowers Institute for Medical Research, Missouri, United States
Kathryn E Malanowski
Stowers Institute for Medical Research, Missouri, United States
Anoja G Perera
Stowers Institute for Medical Research, Missouri, United States
Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, United States
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 cryptic mating type loci and was associated with broad changes in histone modifications and chromatin localization of Sir2 histone deacetylase. The chromatin-silencing defect of disome X can be partially recapitulated by an extra copy of several genes on chromosome X. These results suggest that aneuploidy can directly cause epigenetic instability and disrupt cellular differentiation.
