학술논문
Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies.
Document Type
Academic Journal
Author
Astro V; Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.; Alowaysi M; Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.; Fiacco E; Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.; Saera-Vila A; Sequentia Biotech SL, Barcelona, Spain.; Cardona-Londoño KJ; Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.; Aiese Cigliano R; Sequentia Biotech SL, Barcelona, Spain.; Adamo A; Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
Source
Publisher: Frontiers Media S.A Country of Publication: Switzerland NLM ID: 101630250 Publication Model: eCollection Cited Medium: Print ISSN: 2296-634X (Print) Linking ISSN: 2296634X NLM ISO Abbreviation: Front Cell Dev Biol Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
2296-634X
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.
Competing Interests: AS and RA were employed by the company Sequentia Biotech SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Astro, Alowaysi, Fiacco, Saera-Vila, Cardona-Londoño, Aiese Cigliano and Adamo.)
Competing Interests: AS and RA were employed by the company Sequentia Biotech SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Astro, Alowaysi, Fiacco, Saera-Vila, Cardona-Londoño, Aiese Cigliano and Adamo.)