Abstract:
Numerical chromosomal abnormalities, or aneuploidies, are defined as a gain or loss of chromosomes, usually due to non-disjunction events during meiosis. Most such abnormalities are incompatible with life, as they are catastrophic for genomic stability and cellular health, and often result in miscarriage. In humans, sex chromosome aneuploidies (SCAs) can bypass the previously mentioned issues and, therefore, are among the most common aneuploidies. The clinical manifestations of these syndromes range from intellectual disabilities and metabolic abnormalities to infertility and anatomical defects. In addition, the severity of these symptoms is proportional to the number of extra chromosomes.
Little is known about the molecular etiology behind the phenotype of patients with SCAs. The main topic of this thesis is a gene-to-phenotype correlation study of the transcription factor pair Zinc-Finger protein X-linked (ZFX) and Zinc-Finger protein Y-linked (ZFY), which are encoded by genes located on the X and Y chromosomes, respectively. The gene encoding ZFX can escape X-inactivation and is the only escape gene that encodes a transcription factor. ZFX has been associated with neuroanatomical defects, but not in the context of SCAs. ZFY, on the other hand, while similar in structure to ZFX, has not been associated with neurodevelopmental abnormalities. 
Using male human embryonic stem cells (hESCs) as an in vitro platform, we generated ZFX and ZFY overexpressing lines. These mutant cell lines were characterized and confirmed to produce ZFX or ZFY in an inducible, dose-dependent manner, and thus provide a model of aneuploidy. Differentiation of these cell lines into neural stem cell derivatives was impaired, with a drastic reduction in the neuronal markers SOX2 and NES, and an overall altered cellular morphology compared to control cell lines. These data together imply that the overexpression of ZFX or ZFY impacts neurodevelopment. 
Understanding the specific effect of each gene implicated in SCAs can help to unravel these syndromes’ mechanisms and lead to potential clinical applications.

Bio:
I am working as a master’s student enrolled in KAUST’s MS/PhD program in Bioscience. My research projects include studying the effect of the overdosage of Pseudo-Autosomal Region (PAR) and non-PAR escape genes at the pluripotent state and during differentiation into disease-relevant lineages. I also analyze escape gene overdosage using in vivo mice models. A most fascinating goal would be to find parallels and cross-talks between the two model approaches.

My work aims to contribute to the lab’s goal of understanding and “solving” the transcriptional landscape of sex chromosome aneuploidies. My ambition is that my contribution to these projects may help open avenues for novel and impactful therapeutical approaches.