Define quiescence-associated metabolic programmes in a non-respiring eukaryote and its respiring relative

About the project

About the Project A 2027 Crick-King's College London Joint PhD project with Jurg Bahler (Crick) and Snezhana Oliferenko (KCL). Project background and description Cellular quiescence is an evolutionarily ancient yet understudied strategy characterised by suspended proliferation and increased resilience, enabling long-term viability and reproductive potential under adverse conditions. It is essential for the survival of unicellular organisms in unpredictable environments, and for the developmental plasticity of tissues and organismal homeostasis in multicellular organisms. Quiescent cells reprogram their metabolism to prioritise cell maintenance and stress resistance over growth. Although quiescent cells can remain viable for extended periods, they will inevitably age, featuring a decline in cellular function and loss of proliferative capacity. There is a growing appreciation of the metabolic and phenotypic diversity of cellular quiescent states, but we know little about how cells navigate and exploit this vast functional landscape and how distinct quiescent states affect cell regulation and ageing. Uncovering how quiescence is established and maintained is vital to understanding cellular and organismal physiology, evolution, ageing and associated diseases, as well as mitigating their effects. To investigate the role of metabolic flexibility in the emergence of distinct quiescent cell states, we will exploit two related yeasts, Schizosaccharomyces japonicus and S. pombe, which have evolved fundamentally different metabolic strategies to survive prolonged quiescence. S. pombe is a metabolically flexible obligate aerobe, using both fermentation and respiration for biomass production [1]. During quiescence, it shifts towards respiration, similarly to terminally differentiated mammalian cells, which is essential for longevity [2]. In contrast, S. japonicus does not respire oxygen and features unique metabolic adaptations [3, 4]. Aim 1. Comparing quiescence in populations of both species: We will use high-throughput workflows [5] to map the chronological lifespan and stress resilience of S. japonicus entering quiescence under different physiological conditions, compared to S. pombe. Conditions in which one species underperforms indicate potential trade-offs. We will perform time-resolved transcriptomic, proteomic and metabolomic analyses of cell populations during quiescence induction and ageing. We will uncover condition- and species-specific regulation and metabolic remodelling. Aim 2. Determining spectra of quiescent cell states: Genetically identical cells often diverge into distinct physiological states that may enhance population survival through bet-hedging and metabolic specialisation. We will quantify metabolic heterogeneity during quiescence entry in both species using reporters for ATP, redox state, intracellular pH, autophagic flux, and lipid storage. Cells occupying defined metabolic states will be isolated and tested for lifespan, stress resilience and reactivation capacity. We will determine whether metabolically differentiated cells retain plasticity to transition between alternative quiescent states. To characterise the architecture and dynamics of quiescent landscapes, we will integrate metabolic phenotyping with single-cell RNA sequencing to associate transcriptional programmes with metabolic phenotypes. Once major transcriptional states are identified, we will construct recorders to label cells that have undergone specific transcriptional programmes and to determine how transcriptional history influences subsequent quiescence phenotypes. This PhD project will map the landscape of quiescent states in two closely related, but metabolically divergent species. It will establish, for the first time, how transcriptional history and metabolic state are associated with quiescence outcomes, revealing conserved and species-specific routes to long-term survival. Candidate background This project would suit candidates with a background in cell biology and/or genetics and an interest in fundamental biological questions in cell regulation and physiology, with a focus on the crucial yet understudied quiescent cell states. The candidate will be exposed to a range of state-of-the-art genetic, ‘omics’, cellular, and biochemical assays, as well as the associated computational analyses. Lab-specific question What do you think is one of the most important unanswered questions to understand quiescent cells, and what makes you think it is an important question to investigate?

Research areas