11-13 May 2012 Helsingør - Denmark www.networkbio.org

ROBERT J WEAThERITT1, NORMAN E DAVEY1, TOBY J GIBSON1
1 STRUCTURAL AND COMPUTATIONAL BIOLOGY UNIT, EUROPEAN MOLECULAR BIOLOGY LABORATORY,
MEYERhOfSTRASSE 1, 69117 hEIDELBERG, GERMANY
Linear Motifs confer functional diversity onto splice variants
The pre-translational modification of mRNAs by alternative promoter usage and alternative splicing is an
important source of pleiotropy. Despite intensive efforts, our understanding of the functional implications
of this dynamically created diversity is still incomplete. Using the recent expansion in our knowledge of the
interaction modules within intrinsically disordered regions, we analysed the occurrences of protein modular
architecture within alternative exons. We find that regions affected by pre-translational variation are enriched
in linear motifs and phosphorylation sites suggesting that the modulating of exons containing these interaction
modules is an important regulatory mechanism. In particular, we observe PDZ, PTB and SH2 binding
motifs are particularly prone to be altered between splice variants. We also determine that regions affected
by alternative promoter usage are enriched in IDRs suggesting that protein isoform diversity is tightly coupled
to the modulation of IDRs. This study therefore demonstrates that short linear motifs, and to a lesser
extent phosphorylation sites, are key components for establishing protein diversity between splice variants.
abStractS For PoSterS abStractS For PoSterS
MISS SOPhIE KERShAW, DR. JAMES OSBORNE, PROf. hELEN BYRNE, PROf. DAVID GAVAGhAN.
DEPARTMENT Of COMPUTER SCIENCE, UNIVERSITY Of OxfORD; COLLABORATION WITh ThE WEAThER-
ALL INSTITUTE fOR MOLECULAR MEDICINE, UNIVERSITY Of OxfORD.
Proliferation and Cell Fate in the Colorectal Epithelium
Endemic across the developed world, the prevalence of colorectal cancer (CRC) has not been matched by
equivalent success in pharmaceutical development. Drug failure in clinical trial patients after early-stage
success in laboratory tests motivates a more detailed consideration of the
fundamental differences between in vitro and in vivo cell behaviour. To what extent does tissue geometry
influence expression of the subcellular biochemistry in CRC?
We therefore present a novel framework for in silico translation experiments, enabling experimental hypotheses
to be explored through simulations of colorectal tissue. Developed in collaboration with biochemists
at the Weatherall Institute of Molecular Medicine, we provide a representation of colorectal tissue that incorporates
mathematical equations to govern the biochemical behavior of its constituent cells. Our focus rests
on models for two key pathways implicated in early-stage CRC, namely Notch (involved in cell fate specification)
and Wnt (a governor of proliferation).
We present our model for Notch and Wnt signalling, based upon existing models in the literature, and incorporate
crosstalk between the two pathways. We will discuss an embedding of our model within cells of both
monolayer and colorectal geometries, discussing the spatial constraints imposed in these two scenarios and
demonstrating the resultant cell patterning and proliferative behaviour.
This work presents a new approach to CRC modelling on several counts. Firstly, via the inclusion of crosstalk
between Notch and Wnt pathways to demonstrate coupled control over proliferation and lineage decisions.
This research also represents a novel development in modelling the
Notch-Wnt interaction in situ, in its application of multiscale frameworks to examine the impact of tissue
configuration.
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