Comparative Transcriptome Analysis Reveals Molecular Characteristics of Hutchinson-Gilford Progeria Syndrome in Humans, Monkeys, and Mice (PRJCA020773)
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare condition characterized by premature aging symptoms appearing in childhood. Unfortunately, there is currently no cure for HGPS, emphasizing the need to comprehensively investigate the underlying mechanisms of the disease. The occurrence and development of HGPS are very complex, and in-depth exploration of the pathogenesis and therapeutic mechanism of the disease cannot and should not be conducted on patients. By studying various diseases and life phenomena in animals, we can apply them to humans, hoping to cure HGPS and extend human lifespan. At present, many studies have constructed monkey and mouse models of HGPS to study this disease, but the correlation between different models is low, resulting in a lack of comprehensive understanding of HGPS. Therefore, it is urgent to evaluate the similarities and differences between the current model and human diseases, providing reference for the treatment of HGPS patients. To assess the relevance of these model animals to HGPS patients, we collected transcriptomic data from individuals with HGPS patients, as well as from monkeys and mice. Through this comparative analysis, we found that both HGPS patients and models upregulated inflammation related pathways and downregulated the wnt signaling pathway. The differentially expressed genes are involved in the PI3K/AKT/mTOR pathway and regular cell cycle progression, signaling, apoptosis, and gene regulation. Our analysis of alternative splicing revealed a distinct set of alternative splicing events that are significantly influenced by HGPS. We discovered that these alternative splicing events have an impact on the PISA structural domain of the PAXX protein. This alteration in the PISA domain directly affects the ability of HGPS patients to repair DNA damage. In addition, we identified five promising small molecules (T-98475, WYE-354, torin-1, triflupromazine, latrunculin-b) as potential therapeutic options for HGPS. Overall, our study not only highlights the resemblances between HGPS model species and patients but also offers a convenient approach to studying the disease using these model species.