Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies.
Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies.
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DOI：
10.3389/fcell.2021.801597
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发表时间：
2021
影响因子：
5.5
通讯作者：
Adamo A
中科院分区：
文献类型：
--
作者：
Astro V;Alowaysi M;Fiacco E;Saera-Vila A;Cardona-Londoño KJ;Aiese Cigliano R;Adamo A
Klinefelter综合征（KS）是男性中最常见的非整倍体，其特征在于47，XXY核型。性染色体非整倍性（HGA）也可能发生。在这里，使用KS和HGA诱导的多能干细胞（iPSC）携带49，XXXXY，48，XXXY和47，XXY核型的典型队列，我们确定了假常染色体区域1（PAR 1）内的基因最容易受到剂量依赖性转录失调的影响，因此可能导致更高级别X非整倍性表型的逐渐恶化。相比之下，双等位基因表达的非PAR逃逸基因在iPSC和分化的衍生物中显示出高的克隆间和患者间变异性，表明这些基因可能与可变的KS性状相关。通过以单细胞分辨率询问KS和HGA iPSC，我们表明PAR 1和非PAR逃逸基因不仅对X-非活性特异性转录物（XIST）介导的失活具有弹性，而且它们的转录调控与绝对XIST表达水平脱节。最后，我们探讨了X染色体过量对常染色体的转录影响，并确定了核呼吸因子1（NRF 1）作为锌指蛋白X连锁（ZFX）的关键调节因子。我们的研究提供了第一个证据，X剂量敏感的常染色体转录因子调节X连锁基因在低和高级别的X非整倍体。
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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影响因子：
7.3
作者：
Disteche CM
通讯作者：
Disteche CM
自闭症谱系障碍与49，Xyyyy：案例报告和文献综述。
影响因子：
--
作者：
Demily C;Poisson A;Peyroux E;Gatellier V;Nicolas A;Rigard C;Schluth-Bolard C;Sanlaville D;Rossi M
通讯作者：
Rossi M
影响因子：
8.8
作者：
Bar, Shiran;Seaton, Lev Roz;Benvenisty, Nissim
通讯作者：
Benvenisty, Nissim
影响因子：
3.7
作者：
Bushnell B;Rood J;Singer E
通讯作者：
Singer E
影响因子：
5.8
作者：
Bojesen, A;Juul, S;Gravholt, CH
通讯作者：
Gravholt, CH