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PhD position at the University Grenoble-Alpes

Modeling the information transfer between metabolism and  epigenetics

Funded PhD project


The Computational and Mathematical Biology Group at  TIMC-IMAG lab is seeking outstanding candidates in the area of  quantitative/physical/mathematical/computational biology for a PhD  fellowship  in Grenoble, starting Fall 2018 and working on the  coupling between metabolism and epigenetics.

Location: TIMC-IMAG lab (University Grenoble-Alpes, CNRS, Grenoble INP)

Main contacts:  Eric Fanchon: eric.fanchon@univ-grenoble-alpes.fr; Daniel Jost: daniel.jost@univ-grenoble-alpes.fr

Profile and skills required:

Master 2 level (university, engineer school or equivalent) with a major either in  mathematics, physics, computer science, systems or computational biology. Advanced skills in mathematical/physical modeling and in scientific programming. Strong interest in biological and medical applications. Capacity to work in team in an interdisciplinary context.

Keywords: mathematical/physical modeling, stochastic systems, numerical simulations,  systems biology

Project:

A recent paradigm shift defines metabolism not only as a series of mass and energy  conversions, but also as a signaling mechanism. “Information carrying” metabolites  seem to play a central role in modulating epigenetics, the so-called reprogramming of  genetic information by chemical modifications of DNA and histones, finally leading to  altered gene expression. Since metabolism is strongly influenced by environmental  conditions and life-styles, this new concept of metabolo-epigenetics has important and  far-reaching consequences for human health, and is a fast-growing research area.

In this project, we propose to formalize such concept by using mathematical and  physical modeling in close interactions with experimental biologists. While many efforts  have been devoted to model metabolism and epigenetics separately, very few theoretical  approaches have addressed the information transfer between these two important  classes of cellular processes. Combining dynamical systems, stochastic modeling and  information theory, the PhD candidate will develop quantitative, mechanistic  frameworks to investigate the role of metabolism in controlling gene expression via  epigenetic regulation. Advanced numerical simulations will be performed to analyze the  complexity of such approaches. Building on generic models accounting for key
mechanisms, the student will develop novel, universal concepts on the information  transfer between the metabolite/energy supply chains and gene expression via  epigenetic regulation. Of particular interest, will be to understand the impact of limited  metabolic resources on the maintenance of a robust epigenetic information and  memory. Then, the candidate will contextualize these frameworks to specific biological  examples like the role of acetyl-coA metabolites in controlling gene activation via the  acetylation of histone tails. This will be done in close interaction with experimental  biologists (Saadi Khochbin, Institute of Advanced Biosciences; Uwe Schlattner,  Laboratory of Fundamental and Applied Bioenergetics; Univ. Grenoble-Alpes ) and will require to manipulate large-scale ‘omics’ data. We expect this project to formalize new  theoretical notions and biological hypothesis that will be tested experimentally,  improving our current understanding of the metabolo-epigenetic coupling.

Scientific environment:

This PhD project will be part of an international, interdisciplinary consortium called  SyMER (A Systems approach to new paradigms in Metabolic and Epigenetic Regulation)  grouping biologists, mathematicians, physicists, physicians, data scientists and  sociologists around the question of the coupling between metabolism and epigenetics  within a systems biology approach.  Moreover, the PhD candidate will benefit from the excellent scientific environment of the TIMC-IMAG laboratory which gathers scientists and clinicians towards the use of  computer science and applied mathematics for understanding and controlling normal  and pathological processes in biology and healthcare. He/She will have access to local  and regional computing clusters to perform his/her research.

Supervision:

The PhD candidate will be supervised by Eric Fanchon, Daniel Jost and Angelique  Stéphanou, all CNRS Research Associates at TIMC-IMAG laboratory and expert in  mathematical and physical modeling of biological systems. Regular meetings with the  supervisors will be organized to discuss the current achievements and to define the next  scientific objectives. An annual meeting with experts in the domain will be organized to  evaluate the global orientations of the project.

Bibliography:

M.A. Reid, Z. Dai & J.S. Locasale (2017) The impact of cellular metabolism on chromatin  dynamics and epigenetics, Nat. Cell Biol. 19, 1298–1306.
S. Berry, C. Dean & M. Howard (2017) Slow Chromatin Dynamics Allow Polycomb Target Genes to Filter Fluctuations in Transcription Factor Activity, Cell Systems, 4, 1-13.
D. Jost (2014) Bifurcation in epigenetics: implication to development, proliferation and  diseases, Phys. Rev. E, 89, 010701.
M. Zerihun, C. Vaillant & D. Jost (2015) Effect of replication on epigenetic memory and  consequences on gene transcription, Phys. Biol., 12, 026007.
E. Pourcelot, …, E. Fanchon, J.-M. Moulis, P. Mossuz (2015) Iron for proliferation of cell  lines and hematopoietic progenitors: Nailing down the intracellular functional iron  concentration, Biochim. Biophys. Acta, 1853, 1596-1605.

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