ANEUPLOIDY AS A CAUSE OF IMPAIRED CHROMATIN SILENCING AND MATING-TYPE SPECIFICATION IN BUDDING YEAST

Aneuploidy;epigenetics;silencing;Human Genetics and Molecular Biology

Mulla, WahidMichaelis, Susan D. ;

Johns Hopkins University

关键词: Aneuploidy;    epigenetics;    silencing;    Human Genetics and Molecular Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/59137/MULLA-DISSERTATION-2018.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Aneuploidy, the state of having a chromosome number different from a multiple of the haploid number, has been associated with diseases and developmental disorders.The role of aneuploidy in human disease pathology, especially in cancer, has been a subject of much attention and debate over the last century due to the intrinsic complexity of the phenomena and experimental challenges. 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 my PhD studies, first I did a literature review on the contribution of studies in yeast to current knowledge about aneuploidy with special emphasis on experimental features making yeast a simpler and efficient model to investigate the complex questions in the field of aneuploidy (Chapter 2). Over the last decade, yeast has been an invaluable model for driving discoveries about the genetic and molecular aspects of aneuploidy. Understanding of aneuploidy has been significantly improved owing to the methods for selectively generating aneuploid yeast strains without causing other genetic changes, techniques for detecting aneuploidy, and cutting-edge genetics and ;;omics’ approaches. In this review, we discuss the contribution of studies in yeast to current knowledge about aneuploidy.Special emphasis is placed on experimental features which make yeast a simpler and efficient model to investigate the complex questions in the field of aneuploidy.In second part (Chapters 3 and 4), I performed genetic analyses revealing that purely quantitative changes in the relative copy number of chromosomes can be sufficient to disrupt the epigenetic mechanisms that define the cells;; differentiated state. 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.Our findings provide the causal evidence that aneuploidy is a source of epigenetic instability. It may thus be worth exploring a potential linkage between epigenetic dysregulation and chromosome copy number alterations observed in cancer. The aneuploidy-induced changes in heterochromatin inheritance and histone-modification landscape may be an important mechanism by which chromosomal instability drives large-scale phenotypic variability during tumor evolution.