Immortality refers to the concept of living forever or having an endless lifespan. The idea of immortality has fascinated human beings for centuries. In this project, we aim to investigate the molecular mechanisms responsible for T. dohrnii's biological immortality. Turritopsis dohrnii, also known as the 'immortal jellyfish,' is a species of jellyfish that can revert to its juvenile form after reaching sexual maturity, potentially enabling it to live forever. This unique ability is due to trans-differentiation, a process where fully differentiated cells in the adult jellyfish convert into undifferentiated stem cells, allowing the jellyfish to regenerate its cells and tissues and effectively reverse the ageing process. While the molecular mechanism of T. dohrnii's trans-differentiation is not well understood, recent genomic analysis has revealed extensive changes in gene expression profiles and duplications of genes essential for DNA repair during rejuvenation. However, no single gene granting T. dohrnii immortality has been identified, suggesting that a more complex molecular program is required for rejuvenation.?Mammalian somatic cells can also be forced to lose their cellular differentiation state and get induced into a pluripotent state. Whilst the reprogramming is initiated by the expression of a few regulatory factors, an extensive global reprogramming of epigenetic and transcriptional profiles is necessary for cells to dedifferentiate. This involves significant changes in DNA methylation and histone modification profiles, which adjust the cell's transcriptional profile and thus drive cellular dedifferentiation.?Functionally, the trans-differentiation of Turritopsis cells during rejuvenation resembles the reprogramming of mammalian cells to pluripotency, suggesting that the 'immortal jellyfish' genome also needs to undergo global changes to reset its epigenetic state. However, as the epigenetic mechanisms in Turritopsis are unexplored, it is not clear which specific epigenetic marks play a role in rejuvenation nor which epigenetic mechanisms are responsible for driving this process. We also do not know if epigenetic changes can drive the process, or are they simply a consequence of it? Finally, it is unclear whether the rejuvenation ability of Turritopsis could be mediated solely by epigenetic mechanisms.?Our first goal is to understand the epigenetic system of this unique jellyfish.?For this, we will investigate the genomic distribution of key epigenetic marks and examine their correlation with transcriptional activity to pinpoint the fundamental principles of Turritopsis' epigenetic regulation. For this, we will use state-of-the-art epigenomic and transcriptomic methods to investigate DNA methylation profiles and identify genomic locations where methylation is actively removed. We will study histone modification patterns?to understand their crosstalk with DNA modifications and effects exerted on gene regulation. Once we understand the fundamental principles of the Turritopsis epigenetic system, we will identify the epigenetic programme responsible for driving rejuvenation.For this,together with our partners at Aquarium de Paris,we will initiate Turritopsis rejuvenation and gather jellyfish at consecutive stages of trans-differentiation and study the epigenetic and transcriptional changes driving rejuvenation.Overall,in this project, we will reveal the epigenetic and transcriptional profiles and identify the key epigenetic factors involved in the process.This work will provide a fundamental understanding of the epigenetic system and its transcriptional regulation in Turritopsis dohrnii that will set the stage to guide future research to elucidate the causative roles and molecular mechanisms of rejuvenation. The results obtained in this study will also illuminate the evolution and adaptability of the epigenetic machinery and provide a reference epigenome for future studies.