Biophysical Modeling of Translation in Cancer Cells
Résumé
The translation apparatus has long been viewed as a mere factory until recent findings this last
decade have unraveled its unexpected role in orchestrating real time gene regulation. Far from
being a molecular monolith, the ribosome displays a remarkable h
eterogeneity along with a
striking ability to orchestrate real
-
time control of gene expression. In the meantime, several
reports connect alteration of the translation machinery with elevated cancer risk as well as in
tumor initiation and progression. We ai
m to decipher the variety of translation mechanisms by
modeling dedicated Ribo
-
sequencing experiments. We have designed a new set of Ribo
-
seq
experiments with purified polysomes in order to understand the role of the ribosome density
onto translation and t
o characterized biophysical parameters of translations (hopping rates of
ribosomes, initiation rate, termination rate). Preliminary data will be modeled as a proof of
concept to pave the way to a genome wide analysis with morefinely regulated genes in
cha
rge,
e.g., for cell phenotype. After a presentation of the physical perspective of translation, I will
discuss the usefulness of biophysical modeling approaches to estimate the codon
-
dependent
hopping, initiation and termination rates of ribosomes from Rib
o
-
seq data. I will discuss
designed Ribo
-
seq experiments (purified polysomes) obtained at IGF suggesting that the
ribosome dynamics depends on various conditions: modified dynamics of the first ribosome
entering the newly transcripted mRNA, different parad
igms for translation (cytoplasmic versus
membrane translation), effect of inhomogeneous hopping rates on ribosome traffic etc. Finally,
I will consider how these findings will help to understand the epithelial
-
mesenchymal
transition: we have performed desi
gned Ribo
-
seq experiments inducing a change of the
ribosomes concentration level in vivo in tumor human cells and observed induced change of
phenotype to mezenchymal cells.
