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.长期以来，非整倍体（aneuploidy）与表观遗传改变均被证实与致癌作用相关，但此前尚未明确非整倍体是否会破坏细胞分化所需的表观遗传状态。本研究发现，酵母中约3%的随机非整倍体核型会在细胞增殖过程中破坏沉默染色质的稳定遗传。核型分析显示，该表型与3号染色体及X染色体的拷贝数增加显著相关。仅X染色体二体性即可破坏染色质沉默效应与酵母交配型特征，这一点可通过酵母对信息素缺乏生长响应得到验证。该沉默缺陷不仅局限于隐蔽交配型位点，还与全局组蛋白修饰变化以及Sir2组蛋白去乙酰化酶的染色质定位异常相关。通过增加X染色体上数个基因的拷贝数，可部分重现X染色体二体性所引发的染色质沉默缺陷。上述结果表明，非整倍体可直接引发表观遗传不稳定，并破坏细胞分化过程。