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Quantitative Gene Expression

Samuel Marguerat

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Medical Research Council (MRC)
Living cell must generate sufficient amounts of biomolecules to reach and maintain an optimal size. Cell size is related to function and can span orders of magnitudes from tiny lymphocytes to giant neurons. Accurate size control requires careful coordination of growth and division. While control of the progression through the cell-cycle has been extensively studied, much less attention has been devoted to mechanisms controlling cell growth and cell size. This is a very important problem because understanding how cells generate biomass is indispensable to decoding how cells function. It is also directly relevant to medical research because de-regulated growth is deleterious with pathologies such as cancer, or cardiac hypertrophy. Cell growth has universal and profound implication for the control of gene expression. The number of molecules a cell must produce and maintain depends on its size and on the rate at which it creates biomass. Therefore growth is a dynamic process that necessitates continuous adjustments of gene expression. Moreover, growth and division cycles generates fluctuations in molecules number that affect cellular physiology. Our goal is to understand how the complex interplay between growth and gene expression affects cell physiology and phenotypic diversity. Our programme integrates experimental and computational approaches to study how growth and size interact with gene expression and phenotypic variability. We approach this problem from two complementary angles in cells populations and single cells. We aim at identifying how global genome expression is adjusted to increased demand in RNA and protein numbers when cells grow. We identify factors that limit growth, and study cellular economics during normal and extreme growth. We also investigate the interplay of cellular metabolism with chromatin structure during growth. Together, this will help identifying how optimal growth is achieved. In the second half of our program, we use single cell approaches to investigate the crosstalk between cell growth, transcriptional noise and phenotypic heterogeneity. We analyse cells growing at different rates to identify cellular features that regulate phenotypic heterogeneity. We also analyse the transcriptomes of single cells growing at different rates and dividing at different size to understand how gene expression variability relates to phenotypic heterogeneity. Finally we investigate the influence of transcriptional and post-transcriptional layers of regulation on gene expression noise as growth and size vary. Together our programme will shed light on the complex interplay between growth cell size and gene expression.

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