Wednesday, February 5, 2025
2/5/2025
Project Summary Caloric restriction and reduced mTOR signaling mitigate the adverse effects of aging. They do not translate into effective anti-aging therapies though, because diets are difficult to maintain and mTOR inhibitors exhibit undesirable side effects. The transcription factor CEBPB drives many of the undesirable effects of aging downstream of the TOR pathway. The levels of its short isoform called LIP increase with age; loss of LIP increases lifespan and provides health benefits, while expression of LIP alone increase tumorigenicity. Reprogramming CEBPB and LIP therefore holds great promise as a tool to control aging. Pioneering studies indicated that LIP activates transcription of its target genes, while the canonical long isoform of CEBPB, LAP, is a transcription repressor. Recent evidence draws a more complex picture: - both isoforms are extensively modified by phosphorylation, acetylation (and many others), and those modifications impact their activity; - dimerization of CEBPB with other factors impacts its function; - finally, LIP rescues CEBPB knock-out, suggesting that LIP is not simply a dominant negative inert isoform. Understanding how these regulatory dimensions are integrated by CEBPB isoforms is a pre-requisite to develop technologies able to reprogram aging. Here, we deploy synthetic biology approaches in order to dissect how the CEBPB isoforms, their dimerization partners and post-translational modifications impact the nuclear dynamics of CEBPB and its transcription regulation activity. We also develop synthetic tools to visualize and perturb the LAP:LIP ratio in individual cells. Being able to perturb aging regulators in single cells will enable measuring the contributions of cell-autonomous aging phenotypes and those driven by signals between cells. It will also provide precise tools to dissect one of the common hallmarks of aging: increased heterogeneity of expression.
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