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dc.contributor.advisorAdamo, Antonio
dc.contributor.authorAlowaysi, Maryam
dc.date.accessioned2021-08-31T13:38:35Z
dc.date.available2021-08-31T13:38:35Z
dc.date.issued2021-08
dc.identifier.doi10.25781/KAUST-XHO1A
dc.identifier.urihttp://hdl.handle.net/10754/670867
dc.description.abstractKlinefelter 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.
dc.language.isoen
dc.subjectKlinefelter syndrome
dc.subjectiPSCs
dc.subjectX chromosome inactivation
dc.subjectgene-dosage
dc.subjectpseudo-autosomal region
dc.subjectescape genes
dc.titleAn iPS-Based Approach to Study the Transcriptional and Epigenetic Consequences of X-Chromosome Aneuploidies
dc.typeDissertation
dc.contributor.departmentBiological and Environmental Science and Engineering (BESE) Division
dc.rights.embargodate2022-09-01
thesis.degree.grantorKing Abdullah University of Science and Technology
dc.contributor.committeememberLi, Mo
dc.contributor.committeememberMahfouz, Magdy M.
dc.contributor.committeememberBattaglioli, Elena
thesis.degree.disciplineBioscience
thesis.degree.nameDoctor of Philosophy
dc.rights.accessrightsAt 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.
refterms.dateFOA2021-08-31T13:38:36Z
kaust.request.doiyes


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