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Title: Phenomenological modelling of the fission yeast cell cycle based on multi-dimensional single-cell phenotypic data across growth conditions
Author: Ficorella, Lorenzo
ISNI:       0000 0004 7963 7556
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Cell populations achieve size homoeostasis by coordinating cell growth and division. Direct (sizer) or indirect (adder, timer) models of size regulation have been proposed. Early experiments from 1970s showed that fission yeast implements an almost perfect sizer, whereas more recent data hint at looser regulation. It is unclear whether external conditions can affect regulation stringency and putative additional internal thresholds or timers regulating cell cycle progression. Moreover, it is currently unclear what causes different size heterogeneity levels observed by varying experimental conditions. In this work, I implemented an experimental and computational pipeline to investigate the aforementioned points. First, I created a cell cycle reporter strain and devised an imaging pipeline for analysing cells images, which I employed for acquiring high-throughput phenotypic data on cells grown in different experimental conditions (nitrogen sources). Second, I wrote cell cycle models and optimization scripts for extracting additional dynamic information from static experimental data, e.g. regarding cell size regulation. Apart from confirming that fission yeast adopts an imperfect sizer mechanism (at the G2/M transition), I unexpectedly observed that sizer stringency increases in faster-growing populations and is responsible for the reduction in heterogeneity of cell length at division. I also found that a constant adder regulates G1 elongation and a timer determines S duration. Fission yeast cells elongate asymmetrically; I found that elongation asymmetry depends on growth rate and on the stage in which cells divided. I also observed the presence of slower growing subpopulations, whose rate ranges between 15-40% of the overall growth rate and whose abundance increases in least favourable conditions. Finally, I found that the duration of the non-elongating phase between mitosis and cell division depends on growth rate, as well as the duration of cell cycle stages in the elongating phase and the duration of the mitotic phase.
Supervisor: Marguerat, Samuel ; Shahrezaei, Vahid Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral