LEF1 isoforms regulate cellular senescence and aging

• Published in: Aging cell Vol. 22; no. 12; pp. e14024 - n/a
• Main Authors: Jia, Minxue, Sayed, Khaled, Kapetanaki, Maria G., Dion, William, Rosas, Lorena, Irfan, Saad, Valenzi, Eleanor, Mora, Ana L., Lafyatis, Robert A., Rojas, Mauricio, Zhu, Bokai, Benos, Panayiotis V.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2023; John Wiley and Sons Inc
• Subjects: Age; Aged; Aging; Aging - genetics; Animals; Automation; Cell culture; Cells; cellular senescence; Cellular Senescence - genetics; Comparative analysis; Datasets; Fibrosis; Gene expression; Gene regulation; Histopathology; Humans; IPF; Isoforms; LEF1; lung; Lung - pathology; Lung diseases; Lungs; Lymphocytes T; Lymphoid Enhancer-Binding Factor 1 - genetics; Lymphoid Enhancer-Binding Factor 1 - metabolism; Macrophages; Mice; Protein Isoforms - genetics; Senescence; lung; cellular senescence; aging; IPF; LEF1
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.14024

The study of aging and its mechanisms, such as cellular senescence, has provided valuable insights into age‐related pathologies, thus contributing to their prevention and treatment. The current abundance of high‐throughput data combined with the surge of robust analysis algorithms has facilitated novel ways of identifying underlying pathways that may drive these pathologies. For the purpose of identifying key regulators of lung aging, we performed comparative analyses of transcriptional profiles of aged versus young human subjects and mice, focusing on the common age‐related changes in the transcriptional regulation in lung macrophages, T cells, and B immune cells. Importantly, we validated our findings in cell culture assays and human lung samples. Our analysis identified lymphoid enhancer binding factor 1 (LEF1) as an important age‐associated regulator of gene expression in all three cell types across different tissues and species. Follow‐up experiments showed that the differential expression of long and short LEF1 isoforms is a key regulatory mechanism of cellular senescence. Further examination of lung tissue from patients with idiopathic pulmonary fibrosis, an age‐related disease with strong ties to cellular senescence, revealed a stark dysregulation of LEF1. Collectively, our results suggest that LEF1 is a key factor of aging, and its differential regulation is associated with human and murine cellular senescence. Lymphoid enhancer‐binding factor 1 (LEF1) regulon is a common mechanism of aging in human and murine lungs and in human blood. Experimental evidence supports a direct functional role of the long LEF1 isoform in partially reversing cellular senescence through a possible new regulatory mechanism. LEF1 expression and regulon activity in IPF suggest a diverse mode of action during the early and late stages of the disease.