The disease modeling of Jacob Syndrome reveals an aberrant genome-wide expression modulation from the Y chromosome [RNA-seq]

Male sex chromosome aneuploidies are frequent genetic aberrations in humans characterized by additional X or Y complements in the contest of a 46,XY karyotype. Among male aneuploidies, Klinefelter (KS) and Jacob Syndromes (JS), carrying 47,XXY and 47,XYY chromosomes, respectively, share several clinical features, including sterility, hormonal deficits, neurocognitive delay, and skeletal-muscle defects. In this study, we generated and characterized the inaugural cohort of 47,XYY human induced pluripotent stem cells (iPSCs). We profiled the transcriptome of fibroblasts, iPSCs, and iPSCs-derived neural stem cells (NSCs) to investigate the transcriptional consequences of Y chromosome overdosage across three different cell types. Our data defined subsets of genes sensitive to Y dosage that includes i) non-PAR Y-linked (NPY) genes shared among cell types, ii) genes residing on the X and Y pseudo-autosomal region 1 (PAR1), and iii) autosomal genes that display a mild degree of tissue-specificity. By comparing the expression and identity of PAR1 in KS and JS-derived cells, we confirmed their obligate dosage sensitivity to sex chromosome numbers in a cell type-dependent fashion, and we proved that PAR1 genes are differentially expressed from X and Y chromosomes. We also defined a shared transcriptional signature in X and Y aneuploidies, by comparing sex and autosomal dysregulated genes, that could explain the shared clinical manifestations in JS and KS patients. Furthermore, we demonstrated a regulatory function of NPY genes on their non-PAR homologs on the X chromosome (NPX). By mechanistically linking the expression of X and Y gene pairs, we revealed that NPY genes in overdosage negatively modulate in trans the transcription of their NPX homologs. Finally, we assessed the genome-wide methylation status in cells carrying Y aneuploidies and defined that the additional Y chromosome does not dramatically alter the global DNA methylation status. Our findings expand the knowledge on X and Y chromosome cross-modulation and impact on human gene expression, and suggest that disease modeling of sex aneuploidy through iPSCs may provide an ideal platform for understanding the global effects of aneuploidies in disease-relevant cell types.