Objective: To identify differentially expressed genes and enriched gene sets in a neuronal model of X-linked dystonia-parkinsonism (XDP, DYT3).

Background: The putative dysfunctional gene in XDP is the TATA box-binding protein-Associated Factor 1 (TAF1), located on Xq13.1. Because this gene is intimately involved in the cellular transcription machinery, computational analysis of expression profiling experiments may reveal insights into molecular disease mechanisms occurring transcriptome-wide.

Methods: Induced pluripotent stem cells were reprogrammed from skin biopsies obtained from XDP patients (n=2) and controls (n=2), then differentiated into neurons using lentiviral delivery of transcription factors. Neurons (n=8) were then subjected to microarray-based expression profiling using the Agilent Sureprint Human Gene Expression microarray. Data was analysed using bioinformatic tools to reveal enriched pathways, transcription factors, miRNAs, locations, and gene sets.

Results: 219 genes were upregulated in the XDP group and 132 were downregulated at q-valueFDR</=0.10. Potential gene markers identified included three significantly upregulated genes in the XDP group, discovered by location enrichment analysis to all lie in Xq28. Pathway analysis revealed enrichment of various metabolic (sulfur, carbon, folate) pathways, and Wnt-Notch signalling. The TATA-binding protein transcription factor had the highest enrichment score in the set of downregulated genes (p<0.01), while the miRNA mir-25/32/92/92ab/363/367 was enriched among the upregulated genes. Gene Set Enrichment Analysis additionally identified enrichment of genes involved in the turnover of G-proteins, GTPase, and Ras-binding (p<0.01).

Conclusions: Neuronal models derived from endogenous stem cell lines present a unique opportunity to study disease mechanisms in neurologic diseases, such as XDP. Expression profiling in these cells can be used to discover differentially expressed genes and reveal transcriptome-wide changes and neuron-specific processes, which would otherwise be difficult to achieve using inaccessible brain tissue.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/computational-analysis-of-expression-profiling-data-in-a-neuronal-model-of-x-linked-dystonia-parkinsonism/