Klinefelter Syndrome (KS) is a multisystemic disorder associated with a plethora of
phenotypic features including mental retardation, cardiac abnormalities, osteoporosis,
infertility, gynecomastia, type two diabetes and increased cancer risk. KS is the most
common aneuploidy in humans (with a prevalence of 1:500 to 1:1000 born males) and is
characterized by one or more supernumerary X-chromosomes (47-XXY, 48-XXXY, and
49-XXXXY karyotypes). While X-chromosome inactivation (XCI) represses extra Xs, few
genes called “escape genes” elude the XCI mechanism and are actively transcribed from
X inactive. The overdosage of escape genes has been considered the molecular landscape
that underlies KS clinical features.
In this project, we exploit an integration-free reprogramming method to generate the largest
described cohort of iPSCs from seven patients with KS and healthy donor fibroblasts from
two relatives. The unicity of this cohort relies on the derivation of 47-XXY iPSCs and their
isogenic 46-XY healthy counterparts, along with multiple rare 48-XXXY and 49-XXXXY
iPSC lines. Through X chromosome inactivation (XCI) assessment, we show consistent
retention of n-1 XCI in all derived KS-iPSCs. We identify the genes within the PAR1
region as the most susceptible to dosage-dependent transcriptional dysregulation and
therefore putatively responsible for the progressively worsening phenotype in higher grade X aneuploidies. Moreover, we explore the transcriptional impact of X overdosage on
autosomes and identify that the X-dosage-sensitive autosomal transcription factor NRF1 is
a master regulator of the X-linked escape gene ZFX. Finally, we dissect the potential
pathological impact of the escape gene KDM6A on low- and high-grade supernumerary X
iPSCs and differentiated derivatives. We highlight a considerable proportion of KDM6A
targets that could be responsible for paradigmatic clinical manifestations of KS.
| Identifer | oai:union.ndltd.org:kaust.edu.sa/oai:repository.kaust.edu.sa:10754/670867 |
| Date | 08 1900 |
| Creators | Alowaysi, Maryam |
| Contributors | Adamo, Antonio, Biological and Environmental Science and Engineering (BESE) Division, Li, Mo, Mahfouz, Magdy M., Battaglioli, Elena |
| Source Sets | King Abdullah University of Science and Technology |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Rights | 2022-09-01, At the time of archiving, the student author of this dissertation opted to temporarily restrict access to it. The full text of this dissertation will become available to the public after the expiration of the embargo on 2022-09-01. |
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