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FRIMEDBIO-Fri med.,helse,biol

The nutritional regulation of cellular quiescence in animals

Alternative title: Den ernæringsmessige reguleringen av cellulær quiescence i dyr

Awarded: NOK 7.9 mill.

In most animals feeding determines growth and cell division rates. When food runs out, cells stop dividing and enter 'quiescence', a state of reduced cellular and metabolic activity. Upon re-feeding, cells are reactivated and resume cell divisions again. How nutrient levels control and induce cellular quiescence or cell cycle re-entry is poorly understood. The NutriQui project aims to study how basic cellular activities, gene expression levels and genome organisation change during the transition between quiescence and cell division in a sea anemone. The study will provide a richer molecular and cellular understanding of the quiescence state and its regulation by nutrient abundance. Researching how nutrients regulate animal growth and cell division has been difficult because growth in adult humans and most genetic model organisms has become independent from feeding rates. Growth in sea anemones, in contrast, reacts strongly to the presence or absence of food: while starvation induces quiescence and body shrinkage, refeeding leads to the resumption of cell division and body growth. Sea anemones thereby constitute a powerful genetic research system to characterise the cellular, molecular and genomic changes during feeding-induced cell cycle and growth resumption in the frame of NutriQui. The project will provide novel insights into cellular quiescence as a fundamental but poorly understood process that underlies the ability of many animals (e.g. fish, crabs, clams) to flexibly control growth depending on the availability of resources. This ability is the basis for high body plasticity and life-long growth in many animals. In addition, the project will further our understanding of cellular quiescence as a cellular state that underlies therapeutic challenges such as antibiotics resistance of pathogens, or the chemotherapy escape of cancer stem cells.

Many animals (e.g. marine fish, molluscs, crustaceans) can grow indeterminately by cell proliferation throughout life. Their adult size is thus largely dependent on food availability. Proliferating cells in these animals can therefore often reversibly arrest ('cellular quiescence') depending on nutrient availability, as seen in many unicellular organisms (e.g. yeast). Most common genetic model organisms (e.g. mammals, insects), however, have a determined adult body size with only few tissues able to adapt their size to nutrient availability (e.g. fat tissue, skin). Due to these limitations, the nutritional control of animal proliferation and quiescence is not well understood. In contrast, the sea anemone Nematostella vectensis shows extreme, nutrient-dependent body and cell cycle plasticity. While fed polyps present high growth and cell proliferation rates, starvation leads to rapid, widespread cell cycle arrest and body shrinkage. This genetically tractable animal will therefore be highly informative to understand the link between nutrient availability and cellular quiescence. Our main objective is thus to characterise the cellular, transcriptional and epigenetic changes occurring during feeding-induced cell cycle re-entry. We will study how starvation duration affects quiescence exit rates by characterising the (i) chronology and (ii) functional hierarchies between key cellular processes such as global transcription and translation, lysosomal activity, Tor signalling activity or cell size changes. In addition, we will explore changes in transcriptome composition and chromatin accessibility between quiescence depths using a combination of bulk & single-cell RNA sequencing as well as ATAC-Seq. Overall, the project will provide fundamentally new insights into nutritional regulation as a basic but widely ignored aspect of animal cell cycle and growth control.

Funding scheme:

FRIMEDBIO-Fri med.,helse,biol