Pseudoautosomal region 1 overdosage affects the global transcriptome in iPSCs from patients with Klinefelter syndrome and high-grade X chromosome aneuploidies
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ABSTRACT: Klinefelter syndrome (KS) is the most prevalent aneuploidy in males and is characterized by one or more supernumerary X chromosomes. Here, using a paradigmatic cohort of KS-inducible pluripotent stem cells (iPSCs) carrying 49-XXXXY, 48-XXXY, and 47-XXY karyotypes, we identified genes within the pseudoautosomal region 1 (PAR1) region 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, 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-iPSCs at single-cell resolution, we showed that PAR1 and non-PAR escape genes were not only resilient to X-inactive specific transcript (XIST)-mediated inactivation but also that their transcriptional regulation was disjointed from the absolute XIST expression level. Finally, we explored the transcriptional effects of X chromosome overdosage on autosomes and identified the transcription factor nuclear respiratory factor 1 as the master regulator of zinc finger protein X-linked. Our findings provided the first evidence of an X-dosage-sensitive autosomal transcription factor regulating an X-linked gene in low- and high-grade X aneuploidies.
ORGANISM(S): Homo sapiens
PROVIDER: GSE152001 | GEO | 2022/02/03
REPOSITORIES: GEO
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