In:
Frontiers in Cell and Developmental Biology, Frontiers Media SA, Vol. 9 ( 2022-2-3)
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.
Type of Medium:
Online Resource
ISSN:
2296-634X
DOI:
10.3389/fcell.2021.801597
DOI:
10.3389/fcell.2021.801597.s001
DOI:
10.3389/fcell.2021.801597.s002
DOI:
10.3389/fcell.2021.801597.s003
DOI:
10.3389/fcell.2021.801597.s004
DOI:
10.3389/fcell.2021.801597.s005
DOI:
10.3389/fcell.2021.801597.s006
DOI:
10.3389/fcell.2021.801597.s007
DOI:
10.3389/fcell.2021.801597.s008
DOI:
10.3389/fcell.2021.801597.s009
DOI:
10.3389/fcell.2021.801597.s010
DOI:
10.3389/fcell.2021.801597.s011
DOI:
10.3389/fcell.2021.801597.s012
DOI:
10.3389/fcell.2021.801597.s013
DOI:
10.3389/fcell.2021.801597.s014
DOI:
10.3389/fcell.2021.801597.s015
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2022
detail.hit.zdb_id:
2737824-X
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