Jiménez-Jiménez Víctor, Sánchez-Cabo Fátima, Schwartz Martin A, Sánchez-Álvarez Miguel, Del Pozo Miguel Ángel
Mechanoadaptation & Caveolae Biology Lab, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
Int J Mol Sci. 2025 Apr 17;26(8):3789. doi: 10.3390/ijms26083789.
CAV1 is a protein-coding gene linked to several disorders, including cancer, lipodystrophy, and cardiovascular diseases. While its ability to respond to various mechanical and metabolic stimuli has been documented, a comprehensive understanding of its physiological regulation in humans is lacking. We leveraged the comprehensiveness of human post-mortem tissue data from the Genotype-Tissue Expression (GTEx) consortium, systematically exploring the sources of variability in CAV1 transcriptional levels using extensive bulk and single-nuclei RNA-seq datasets. This human-centric approach, avoiding inter-species comparisons, constitutes a unique resource to explore CAV1 regulation within the complexity of human tissues. Notably, cell type proportion was identified as a major determinant of CAV1 transcription levels across tissues. Donor physiological conditions, including disease states and end-of-life circumstances, also exhibited a tissue-specific influence. Among primary upstream regulators associated with CAV1, chromatin modifiers stood out, especially SMARCA2, which showed a positive correlation across tissues, and PRC2 complexes, which exhibited tissue-specific correlation. Upstream regulatory networks determining CAV1 levels are also enriched for annotations such as mechanobiology (e.g., TEAD4), immunity (e.g., RELA and STAT3), and metabolism (e.g., MYC and NRF1). A remarkable observation was a strong correlation between CAV1 and the relative infiltration of immune cells across tissues, supporting a potential role for CAV1 as a marker and driver of tissue immune infiltration.
CAV1是一个与多种疾病相关的蛋白质编码基因，这些疾病包括癌症、脂肪营养不良和心血管疾病。虽然已经有文献记载了它对各种机械和代谢刺激的反应能力，但目前仍缺乏对其在人体生理调节方面的全面了解。我们利用了基因型-组织表达（GTEx）联盟提供的人类尸检组织数据的全面性，通过大量的批量和单核RNA测序数据集系统地探索了CAV1转录水平的变异性来源。这种以人类为中心的方法避免了种间比较，构成了在人体组织复杂性中探索CAV1调控的独特资源。值得注意的是，细胞类型比例被确定为跨组织CAV1转录水平的主要决定因素。供体的生理状况，包括疾病状态和临终情况，也表现出组织特异性影响。在与CAV1相关的主要上游调节因子中，染色质修饰因子尤为突出，特别是SMARCA2，它在各组织中呈正相关，以及PRC2复合体，它表现出组织特异性相关性。决定CAV1水平的上游调控网络在诸如力学生物学（如TEAD4）、免疫（如RELA和STAT3）和代谢（如MYC和NRF1）等注释中也很丰富。一个显著的发现是CAV1与跨组织免疫细胞的相对浸润之间存在很强的相关性，这支持了CAV1作为组织免疫浸润的标志物和驱动因素的潜在作用。
