Comprehensive bioinformatics analysis of CAV1 function and regulation in physiological and pathological contexts

• Autores: Víctor Jiménez Jiménez
• Directores de la Tesis: Miguel Ángel del Pozo (dir. tes.), Fátima Sánchez Cabo (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2023
• Idioma: inglés
• Número de páginas: 231
• Títulos paralelos:
  • Abordaje bioinformático global para la caracterización del papel de CAV1 y su regulación en condiciones fisiológicas y patológicas
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • This thesis aims at contributing to a better understanding of the multifaceted roles of caveolin-1 (CAV1), a highly pleiotropic protein with cell-type-specific functions that broadly impacts on organismal homeostasis despite its restricted expression to certain cell types and states. The primary objective of this thesis is to unravel the intricate roles of CAV1 across various tissues, to identify upstream modulating stimuli, and to infer regulators responsible for changes in CAV1 expression in these tissues, as well as the transcriptional changes that arise when CAV1 is deleted or modulated in pathophysiological conditions such as cancer, cardiovascular disease, or epithelial-to-mesenchymal transition (EMT). An unbiased, data-driven strategy was employed to infer CAV1 correlation networks that are tissue and condition-specific. Bulk RNA-seq data from 52 tissues and 948 individuals, and scRNA-seq data from 8 tissues and 16 individuals from the GTEx project were reanalyzed. Additionally, 33 datasets of microarrays and RNA-seq with CAV1 deletion in different tissues and conditions were examined. The role of CAV1 in pathophysiological conditions was further investigated through the reanalysis of FANTOM5 data in carcinoma samples and during EMT induction in ARPE-19 epithelial cells. The analysis of human donor data from the GTEx project revealed that CAV1 regulation exhibits cell-type specificity, and that its transcriptional levels are influenced by various factors, such as the proportion of cell types in the sample and other donor-dependent variables such as their Terminal Phase Context and underlying diseases. Contrary to our initial hypothesis, our unbiased analysis of GTEX data did not identify CAV1 transcriptional regulatory programs specific for caveolae-dense and caveolae-depleted tissues that might explain the different roles and expression of this gene in these different scenarios. The results of the analysis showed that CAV1 might act as a mediator of cell communication or as an inflammation marker, depending on the context. In general, genes correlating with CAV1 in a tissue-specific manner were significantly associated with three functional categories: mechanobiology, immunity, and metabolism. Upon CAV1 gene deletion, compensation mechanisms varied across tissues and conditions, primarily affecting the aforementioned functional categories: mechanobiology, immunity, and metabolism. The main upstream regulators associated with CAV1 are chromatin modifiers, displaying universal associations like SMARCA2 or condition-specific ones like PRC2 members, and transcription factors regulating the previously mentioned functional categories such as TEAD4, RELA, STAT3, and MYC. A Bayesian differential gene expression model was developed to infer changes in cell-type proportions concurrently with alterations in cell-type-specific transcriptomes in the heart transcriptomes of CAV1KO CAV3KO mice. This analysis unravelled that the absence of CAV1 in the heart leads to an increase in fibroblast, endothelial, and immune cell content, supporting a role for CAV1 in inflammation modulation through cell communication mechanisms, as previously observed from the GTEx data. Finally, we investigated the role and regulation of CAV1 in pathological scenarios. CAV1 and caveolar components were found differentially expressed between small cell carcinoma and non-small cell carcinoma, correlating with distinct transcriptional programs. In fact, high levels of CAV1 were found to be associated with mechanoresponsive, inflammatory, and EMT-related pathways, while low levels corresponded to neuroendocrine differentiation signatures. The transcriptional levels of CAV1 dynamically respond to EMT induction in ARPE-19 cells, concurrently regulating cellular metabolism and proliferation during the process. In conclusion, this thesis provides a comprehensive understanding of CAV1 involvement in cellular physiology through a comprehensive approach. The study highlights CAV1’s potential as a promising therapeutic target, particularly in the context of carcinoma and EMT. By identifying upstream regulators of CAV1 and uncovering its multifaceted roles, this research offers valuable insights for future investigations and the development of more effective treatments targeting key CAV1 modulators and related signaling pathways