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

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, 4...

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Autores principales: Astro, Veronica, Alowaysi, Maryam, Fiacco, Elisabetta, Saera-Vila, Alfonso, Cardona-Londoño, Kelly J., Aiese Cigliano, Riccardo, Adamo, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8850648/
https://www.ncbi.nlm.nih.gov/pubmed/35186953
http://dx.doi.org/10.3389/fcell.2021.801597
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author Astro, Veronica
Alowaysi, Maryam
Fiacco, Elisabetta
Saera-Vila, Alfonso
Cardona-Londoño, Kelly J.
Aiese Cigliano, Riccardo
Adamo, Antonio
author_facet Astro, Veronica
Alowaysi, Maryam
Fiacco, Elisabetta
Saera-Vila, Alfonso
Cardona-Londoño, Kelly J.
Aiese Cigliano, Riccardo
Adamo, Antonio
author_sort Astro, Veronica
collection PubMed
description 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.
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spelling pubmed-88506482022-02-18 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 Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2022-02-03 /pmc/articles/PMC8850648/ /pubmed/35186953 http://dx.doi.org/10.3389/fcell.2021.801597 Text en Copyright © 2022 Astro, Alowaysi, Fiacco, Saera-Vila, Cardona-Londoño, Aiese Cigliano and Adamo. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
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
title Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies
title_full Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies
title_fullStr Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies
title_full_unstemmed Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies
title_short Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies
title_sort pseudoautosomal region 1 overdosage affects the global transcriptome in ipscs from patients with klinefelter syndrome and high-grade x chromosome aneuploidies
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8850648/
https://www.ncbi.nlm.nih.gov/pubmed/35186953
http://dx.doi.org/10.3389/fcell.2021.801597
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