Abstract
Klinefelter syndrome (KS) is the most prevalent aneuploidy in males and is characterized by a 47,XXY karyotype. Less frequently, higher grade sex chromosome aneuploidies (HGAs) can also occur. Here, using a paradigmatic cohort of KS and HGA induced pluripotent stem cells (iPSCs) carrying 49,XXXXY, 48,XXXY, and 47,XXY karyotypes, we identified the genes within the pseudoautosomal region 1 (PAR1) as the most susceptible to dosage-dependent transcriptional dysregulation and therefore potentially responsible for the progressively worsening phenotype in higher grade X aneuploidies. By contrast, the biallelically expressed non-PAR escape genes displayed high interclonal and interpatient variability in iPSCs and differentiated derivatives, suggesting that these genes could be associated with variable KS traits. By interrogating KS and HGA iPSCs at the single-cell resolution we showed that PAR1 and non-PAR escape genes are not only resilient to the X-inactive specific transcript (XIST)-mediated inactivation but also that their transcriptional regulation is disjointed from the absolute XIST expression level. Finally, we explored the transcriptional effects of X chromosome overdosage on autosomes and identified the nuclear respiratory factor 1 (NRF1) as a key regulator of the zinc finger protein X-linked (ZFX). Our study provides the first evidence of an X-dosage-sensitive autosomal transcription factor regulating an X-linked gene in low- and high-grade X aneuploidies.
Highlights
Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy in humans with a prevalence of 1:500–1:1,000 in males (Bojesen et al, 2003; Davis et al, 2016)
Our work exploits the recently generated largest cohort of lowand high-grade X aneuploid induced pluripotent stem cells (iPSCs), including genetically matched isogenic, disease, and healthy iPSCs, to shed light on the transcriptional dysregulation associated with supernumerary X chromosomes in early development and disease-relevant cell types
Previous studies on female human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) have shown that X erosion is a key limitation for iPSC-based X aneuploidy modeling approaches and suggested that X reactivation could be an intrinsic iPSC characteristic (Vallot et al, 2015) or acquired during in vitro culturing (Mekhoubad et al, 2012)
Summary
Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy in humans with a prevalence of 1:500–1:1,000 in males (Bojesen et al, 2003; Davis et al, 2016). Common clinical manifestations include infertility, gynecomastia, tall stature, small testes, osteoporosis, and sparse body hair, whereas other features, such as cardiac structural abnormalities, metabolic disorders, type two diabetes, cancers, and intellectual disability, are less frequent (Swerdlow et al, 2001; Lanfranco et al, 2004; Bojesen et al, 2006; Groth et al, 2013; Bonomi et al, 2016). Severe neurodevelopmental and physiological disorders are associated with patients with HGAs (e.g., 49,XXXXY and 48,XXXY) (Tartaglia et al, 2011). The KS and HGAs etiopathology is attributable to sex chromosome non-disjunction during gametogenesis at meiosis I or II. The non-disjunction event results in gametes with abnormal sex chromosome numbers, which in turn leads to an XXY zygote. Nondisjunction during early mitotic division of the zygote results in a mosaic form of KS (Lanfranco et al, 2004; Bonomi et al, 2016)
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