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

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

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

Files

fcell-09-801597 (1).pdf (5.86 MB)

License

http://creativecommons.org/licenses/by/4.0/

Type

Article

Authors

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

KAUST Department

Biological and Environmental Science and Engineering (BESE) Division
Bioscience Program

KAUST Grant Number

BAS 1077-01-01

Date

2022-02-03

Submitted Date

2021-10-25

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.

Citation

Astro, Alowaysi, M., Fiacco, E., Saera-Vila, A., Cardona-Londoño, K. J., Aiese Cigliano, R., & Adamo, A. (2022). Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies. Frontiers in Cell and Developmental Biology, 9. https://doi.org/10.3389/fcell.2021.801597

Acknowledgements

This work was funded by baseline funding (BAS 1077-01-01) to AA and King Abdulaziz City for Science and Technology (KACST) grant to MA and AA (KACST RGC/3/3628).