Super-resolution imaging and modeling of chromosomes in single cells

Super-resolution imaging and modeling of chromosomes in single cells

By In PhD proposals 2018 On April 9, 2018

Project: Super-resolution imaging and modeling of chromosomes in single cells

Laboratory: Imaging and Modeling Unit

Affiliation: Institut Pasteur
Address: Institut Pasteur, 25 rue du Docteur Roux

LAB Director
Name: Christophe Zimmer
Phone number: +33140613891

Name: Christophe Zimmer
Phone number: 0140613891

Subject Keywords: Single molecule imaging, computational biology, artificial intelligence, chromosomes, modeling.
Summary of lab’s interests: Our interdisciplinary lab develops computational and experimental approaches to characterize and quantitatively predict selected cellular processes. Current projects concentrate on investigating the spatial architecture of the genome and its functions (e.g. Arbona et al. Gen Biol 2017, Herbert et al. EMBO J. 2017), and on developing single molecule high resolution imaging techniques, and applying them to questions in cell biology and microbiology (e.g. Lelek et al. PNAS 2012, Mueller et al. Nat Meth 2013, Lelek et al. Nat Comm 2015; Rincheval et al. Nat Comm 2017). Our lab is also active in applying and adapting deep learning methods to analyzing large data sets in biomedical research (Ouyang et al. Nat Biotech 2018).
Project summary: The spatial architecture and dynamics of chromosomes play an important role in gene expression and the maintenance of genome stability. The molecular and biophysical mechanisms underlying chromatin organization are beginning to be understood thanks to a combination of genome-wide techniques (Hi-C) and polymer modeling. However, because Hi-C is mostly a bulk assay, how chromatin fibers fold and move and how this organization influences and is influenced by DNA damage and repair remains unclear. Recently, we have used conventional microscopy and polymer simulations to show that in yeast, DNA damage leads to enhanced chromatin mobility via an increase in chromatin fiber rigidity. However, it remains unclear how chromatin changes locally in different genomic regions upon DNA damage. Therefore, there is a strong need to visualize chromatin fiber structure directly at high resolution in single cells.
The main goal of this project is to image chromosomes in single yeast cells using high resolution 3D fluorescence microscopy approaches and to study how the chromatin fiber (and associated protein complexes) changes during induction of local or global DNA damage. In combination with polymer simulations, this will lead to a better understanding of the biophysical basis of chromatin alterations in the maintenance of genome stability.
Interdisciplinary aspect of the project: The project will combine an experimental effort (labeling and visualizing individual chromosomes) and a modeling and data analysis effort (reconstruction of structures from single molecule image data and predictive polymer simulations) and is therefore fully interdisciplinary.
Funding: The lab does not have prior funding for this PhD project but 3 postdocs are currently working on related projects funded by Equipe FRM and Institut Pasteur.