Spatiotemporal modelling in biology: from transcriptional regulation to plasmid positioning

Ietswaart, Jaldert Hugo Rigobert (2015) Spatiotemporal modelling in biology: from transcriptional regulation to plasmid positioning. Doctoral thesis, University of East Anglia.

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Here I describe how cycles of mathematical modelling and experimenting
have advanced our quantitative understanding of two different
processes: transcriptional regulation of the floral repressor
FLOWERING LOCUS C (FLC ) in Arabidopsis thaliana and spatial
positioning of low copy number plasmids in Escherichia coli. Despite
the diversity in biological subjects, my spatiotemporal modelling approach
provides a common ground.
FLC regulation involves an antisense-mediated chromatin silencing
mechanism, where alternative polyadenylation of antisense transcripts
is linked to changed histone modifications at the locus and altered
expression. Mathematical model predictions of FLC transcriptional
dynamics are validated by measurements of total and chromatinbound
FLC intronic RNA. This demonstrates that FLC regulation involves
a quantitative coordination between transcription initiation
and elongation, potentially a general feature of gene regulation in
a chromatin context. A quantitative analysis of cellular RNA levels
indicates that FLC processing and degradation are well described
by Poisson processes. FLC transcription correlates with cell volume,
which underlies the large cellular variation in transcript levels.
Low copy number plasmids in bacteria require segregation for
stable inheritance through cell division. This is often achieved by a
parABC locus, comprising an ATPase ParA, DNA-binding protein
ParB and a parC region, encoding ParB-binding sites. These components
space plasmids equally over the nucleoid, yet the underlying
mechanism has not been understood. Here I show mathematically
that differences between competing ParA concentrations on either
side of a plasmid can specify regular plasmid positioning. This
can be achieved regardless of the exact mechanism of plasmid movement.
Experimentally, parABC from E. coli plasmid pB171 increases
plasmid mobility, inconsistent with models based on plasmid diffusion
and immobilization. Instead this observation favours a directed
motion model. These results unify previously contradictory models
for plasmid segregation and provide a mechanistic basis for selforganized
plasmid spacing.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Jackie Webb
Date Deposited: 03 May 2016 15:21
Last Modified: 25 Aug 2017 11:27


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