Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies

Veronica Astro; Maryam Alowaysi; Elisabetta Fiacco; Alfonso Saera-Vila; Kelly J Cardona-Londoño; Riccardo Aiese Cigliano; Antonio Adamo

doi:10.3389/fcell.2021.801597

Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies

Front Cell Dev Biol. 2022 Feb 3:9:801597. doi: 10.3389/fcell.2021.801597. eCollection 2021.

Authors

Veronica Astro¹, Maryam Alowaysi¹, Elisabetta Fiacco¹, Alfonso Saera-Vila², Kelly J Cardona-Londoño¹, Riccardo Aiese Cigliano², Antonio Adamo¹

Affiliations

¹ Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
² Sequentia Biotech SL, Barcelona, Spain.

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.

Keywords: Klinefelter syndrome; X chromosome inactivation; escape genes; high-grade X aneuploidies; induced pluripotent stem cells; pseudoautosomal region.