Dion, W. | bioRxiv Science

bioRxiv2023

LEF1 isoforms regulate cellular senescence and aging

BackgroundThe 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. MethodsWith the focus on 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. ResultsWe 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 (IPF), an age-related disease with strong ties to cellular senescence, we demonstrated a stark dysregulation of LEF1. ConclusionsCollectively, our results suggest that the LEF1 is a key factor of aging, and its differential regulation is associated with human and murine cellular senescence.

genomics↗

bioRxiv2023

Evidence for conservation of a primordial 12-hour ultradian gene program in humans

While circadian rhythms are entrained to the once daily light-dark cycle of the sun, many marine organisms exhibit [~]12h ultradian rhythms corresponding to the twice daily movement of the tides. Although human ancestors emerged from circatidal environment millions of years ago, direct evidence of [~]12h ultradian rhythms in humans is lacking. Here, we performed prospective, temporal transcriptome profiling of peripheral white blood cells and identified robust [~]12h transcriptional rhythms from three healthy participants. Pathway analysis implicated [~]12h rhythms in RNA and protein metabolism, with strong homology to the circatidal gene programs previously identified in Cnidarian marine species. We further observed [~]12h rhythms of intron retention events of genes involved in MHC class I antigen presentation, synchronized to expression of mRNA splicing genes in all three participants. Gene regulatory network inference revealed XBP1, and GABP and KLF transcription factor family members as potential transcriptional regulators of human [~]12h rhythms. These results suggest that human [~]12h biological rhythms have a primordial evolutionary origin with important implications for human health and disease.

systems biology↗