Chromosome aneuploidy represents a serious burden on human health. Congenital aneuploidy often results in birth defects while acquired aneuploidy is associated with diseases such as cancer. Additional or missing chromosomes can cause widespread gene expression dysregulation and epigenetic alterations throughout the genome. Our goal is to evaluate the molecular consequences of an abnormal number of X or Y chromosomes. We will focus on two common disorders, Klinefelter (47,XXY) and Turner (45,X) syndromes. In XXY men a single X chromosome remains active while the other is silenced by X inactivation. Despite this, these men have abnormal phenotypes including cognitive defects, in part due to over-expression of genes that escape X inactivation. Conversely, women with a single X chromosome have phenotypic anomalies including cognitive defects and heart abnormalities due to haploinsufficiency for these escape genes. Y-linked genes protect normal XY males from deleterious effects of X monosomy. Thus, both X-linked and Y-linked genes are critically implicated in sex chromosome aneuploidy. To rigorously determine the effects of sex chromosome aneuploidy on global gene expression and on the epigenetic environment we will derive isogenic induced pluripotent stem cell (iPSC) lines (1) by removal of the X or Y chromosome from parental iPSC lines with an XXY karyotype, and (2) by derivation of clonal iPSC lines from mosaic cultures with an aneuploid line. Comparisons between pairs of isogenic lines will circumvent the highly variable genetic background in the human population. To access cell types relevant to phenotypes observed in sex chromosome aneuploidy we will differentiate the iPSCs into neuronal cells and cardiomyocytes. We will then manipulate levels of two candidate X/Y gene pairs, KDM5C/KDM5D and KDM6A/UTY, in the new isogenic lines to delete or add a copy of the X or Y paralogs and determine whether we can recapitulate the effects of X or Y aneuploidy. These candidate genes are of special interest because they represent dosage-sensitive master regulators important for promoter and enhancer regulation and for neural cell and embryo development. We will extend our study in vivo by performing parallel gene expression and epigenetic analyses in brain and heart from mouse models of X aneuploidy including XXY and XO mice in which we will manipulate levels of Kdm5c and Kdm6a. By eliminating the noise of natural genomic variability between individuals we will more precisely assess perturbations of gene expression, epigenetic environment, and phenotypes in aneuploid cells and tissues. This study will contribute to a better understanding not only of aneuploidy but also of the role of the sex chromosomes in sex differences.
Chromosomal aneuploidy is a major cause of congenital or acquired disease. Sex chromosome aneuploidy differs from autosomal aneuploidy due to the peculiar regulation of the sex chromosomes. Our investigation of sex chromosome aneuploidy in terms of disruption of gene expression, chromatin configuration and associated phenotypes will help understand both the mechanisms of this common type of genetic disorders and the role of sex-linked genes in sex differences.
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