{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:21:51Z","timestamp":1787170911984,"version":"build-2736575974"},"reference-count":122,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T00:00:00Z","timestamp":1643846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004054","name":"King Abdulaziz University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004052","name":"King Abdullah University of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3389\/fcell.2021.801597","type":"journal-article","created":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T00:55:37Z","timestamp":1643849737000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies"],"prefix":"10.3389","volume":"9","author":[{"given":"Veronica","family":"Astro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Alowaysi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Fiacco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Saera-Vila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly J.","family":"Cardona-Londo\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Aiese Cigliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Adamo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e0175787","DOI":"10.1371\/journal.pone.0175787","article-title":"Comparative Expression Profiling of Testis-Enriched Genes Regulated during the Development of Spermatogonial Cells","volume":"12","author":"Ahn","year":"2017","journal-title":"PLoS ONE"},{"key":"B2","doi-asserted-by":"publisher","first-page":"102042","DOI":"10.1016\/j.scr.2020.102042","article-title":"Establishment of an iPSC Cohort from Three Unrelated 47-XXY Klinefelter Syndrome Patients (KAUSTi007-A, KAUSTi007-B, KAUSTi009-A, KAUSTi009-B, KAUSTi010-A, KAUSTi010-B)","volume":"49","author":"Alowaysi","year":"","journal-title":"Stem Cel Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"102008","DOI":"10.1016\/j.scr.2020.102008","article-title":"Establishment of iPSC Lines from a High-Grade Klinefelter Syndrome Patient (49-XXXXY) and Two Genetically Matched Healthy Relatives (KAUSTi003-A, KAUSTi004-A, KAUSTi004-B, KAUSTi005-A, KAUSTi005-B, KAUSTi005-C)","volume":"49","author":"Alowaysi","year":"","journal-title":"Stem Cel Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"102098","DOI":"10.1016\/j.scr.2020.102098","article-title":"Generation of Two iPSC Lines (KAUSTi001-A, KAUSTi002-A) from a Rare High-Grade Klinefelter Syndrome Patient (49-XXXXY) Carrying a Balanced Translocation T(4,11) (Q35,q23)","volume":"49","author":"Alowaysi","year":"","journal-title":"Stem Cel Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.stem.2012.03.008","article-title":"Molecular Signatures of Human Induced Pluripotent Stem Cells Highlight Sex Differences and Cancer Genes","volume":"11","author":"Anguera","year":"2012","journal-title":"Cell Stem Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"141","DOI":"10.3389\/fcell.2018.00141","article-title":"Epigenetic Control of Endocrine Pancreas Differentiation In Vitro: Current Knowledge and Future Perspectives","volume":"6","author":"Astro","year":"2018","journal-title":"Front. 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