Final Report Summary - SYSGRO ('Systems' study of cellular growth, shape and polarity)
A major challenge of modern biology is to elucidate how cellular structure and function result from the ‘systemic’ action of the genome and proteome. In this project SYSGRO, we used an ambitious, highly interdisciplinary and integrated approach combining high-content and quantitative microscopy, systematic gene knockouts, and computational/theoretical methods to carry out the most detailed ‘systemic’ study of three key aspects of cellular physiology: growth, shape and polarity. We used the fission yeast Schizosaccharomyces pombe as experimental model organism. The haploid fission yeast – with its relative genomic simplicity, genetic tractability, uniform size and shape of its cells, and well-characterized, conserved and simple growth and polarization machinery – provided an ideal experimental system for this study.
In particular, our main achievements are that:
1) We established a collaborative platform to carry out yeast functional genomics studies using large scale microscopy, arguably the most advanced such platform worldwide.
2) We used that platform to systematically look for the first time through the genome for genes that control and link three fundamental processes: cellular shape, the spatial organisation of microtubule polymers in cells and the way cells progress through the cell division cycle. We identified and gave a proposed function to 262 genes controlling or co-regulating those processes. Of those 150 were newly discovered for those processes, 92 are involved in more than one process and 40 had never been given any function previously. Among many novel findings, we discovered that when cells respond to DNA damage they also modify their microtubule properties. Given that DNA damage and microtubules are the two targets of frontline conventional chemotherapy, this finding could bring new insights of potential biomedical importance.
3) We obtained a wiring diagram of the gene and protein circuit that controls cellular polarity, likely the most complete such network diagram until now.
4) We discovered new fundamental mechanisms allowind cells to control their polarity.
5) We furthered our understanding of how the mechanical properties of cells and their surroundings affect how the cells grow and divide.
Overall we think that a better understanding of the systemic regulation of those processes is likely to contribute in the long run to the development of better strategies to fight cellular pathologies associated with many diseases, such as cancer.
In particular, our main achievements are that:
1) We established a collaborative platform to carry out yeast functional genomics studies using large scale microscopy, arguably the most advanced such platform worldwide.
2) We used that platform to systematically look for the first time through the genome for genes that control and link three fundamental processes: cellular shape, the spatial organisation of microtubule polymers in cells and the way cells progress through the cell division cycle. We identified and gave a proposed function to 262 genes controlling or co-regulating those processes. Of those 150 were newly discovered for those processes, 92 are involved in more than one process and 40 had never been given any function previously. Among many novel findings, we discovered that when cells respond to DNA damage they also modify their microtubule properties. Given that DNA damage and microtubules are the two targets of frontline conventional chemotherapy, this finding could bring new insights of potential biomedical importance.
3) We obtained a wiring diagram of the gene and protein circuit that controls cellular polarity, likely the most complete such network diagram until now.
4) We discovered new fundamental mechanisms allowind cells to control their polarity.
5) We furthered our understanding of how the mechanical properties of cells and their surroundings affect how the cells grow and divide.
Overall we think that a better understanding of the systemic regulation of those processes is likely to contribute in the long run to the development of better strategies to fight cellular pathologies associated with many diseases, such as cancer.