An iPS-Based Approach to Study the Transcriptional and Epigenetic Consequences of X-Chromosome Aneuploidies
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Type
DissertationAuthors
Alowaysi, Maryam
Advisors
Adamo, Antonio
Committee members
Li, Mo
Mahfouz, Magdy M.

Battaglioli, Elena
Program
BioscienceKAUST Department
Biological and Environmental Science and Engineering (BESE) DivisionDate
2021-08Embargo End Date
2022-09-01Permanent link to this record
http://hdl.handle.net/10754/670867
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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.Abstract
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.ae974a485f413a2113503eed53cd6c53
10.25781/KAUST-XHO1A