Marie Curie Training Course of the European Union

NATO Advanced Study Institute

LES HOUCHES SUMMER SCHOOL

MULTIPLE ASPECTS OF DNA AND RNA:

FROM BIOPHYSICS TO BIOINFORMATICS

August 2 - August 27, 2004.

Organisers: D. Chatenay, S. Cocco, O. Krichevsky, R. Monasson, D. Thieffry

1. Overview of the school

2. The lectures

3. The lecturers

4. Tentative schedule

5. Practical information (registration, location, ...

Last update: August 8th, 2004.

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Overview of the School

We organize a Summer School in August 2004, hosted by the Ecole de Physique, Les Houches, French Alps, at the border line between physics, biology and information science. The School is dedicated to the multiple aspects, that is, biological, physical and computational analysis of DNA and RNA molecules. These molecules, central to vital processes, have been experimentally studied by molecular biologists for decades. Recent progresses (e.g. use of DNA chips, manipulations at the single molecule level, availability of huge genomic databases) have revealed an imperious need for theoretical modelling. Physicists have already contributed to this effort, but further progresses will clearly not be possible without an integrated understanding of all DNA and RNA aspects and studies.

The School is primarily intended to provide graduate students and young researchers having a background in physics with up-to-date knowledge in the study of biomolecules and to make them capable of understanding ongoing researches in the field, be they conducted in molecular biology, biophysics or bioinformatics. We also aim to attract some students with biological or mathematical backgrounds desiring to extend their knowledge in the physics of biomolecules. Emphasis will be put on the comprehensive presentation of theoretical concepts and analytical or computer-based tools for DNA and RNA structural modelling, simultaneously with a presentation of experimental techniques and results. Lecturers have been carefully chosen among top-level biologists, biochemists, physicists and experts in bioinformatics since it is our opinion that a real interdisciplinarity cannot be achieved otherwise.

The School will be chronologically divided in three main sections, with essentially equal durations:

Section 1: Biochemistry and Biology of DNA/RNA

Section 2: Biophysics: from Experiments to modelling and theory

Section 3: Bioinformatics

Section 1 will aim at giving students necessary knowledge on the structure and function of nucleic acids, and of biological processes such as transcription, replication, ... involving DNA and RNA molecules in the cell. Special attention will also be paid to experimental characterization techniques such as spectroscopy, NMR, neutron scattering.

Section 2 will cover the biophysics of DNA and RNA, starting from basics in polymer physics. A large space will be devoted to a parallel presentation of recent experimental and theoretical progresses in the field of single molecule studies. Single molecule experiments will be put into perspective with comparison to biological bulk experiments. Recent advances in the field of electrophoresis will also be described from a biophysical point of view.

Section 3 will present recent computational approaches to integrate, analyse and simulate molecular and genetic data on the structure of nucleic acids, as well as on the regulation of their expression and activity. The analysis of genetic regulatory networks will be devoted a large space. We will also organize for the students a series of computer-lab work to illustrate the program of this bioinformatics section.

Special care will be brought to ensure a coherent presentation of concepts from different disciplines and to provide attendants with a synthetic and global vision of DNA and RNA studies.

We will follow the well-proven Les Houches format. Lectures will last 1.5 hours, with two lectures in the morning and one in the afternoon. This schedule leaves time for ample personal work. The limited number of main lecturers will make lectures series long enough to explain things carefully. Complementary conferences will take place in the evenings; some slots will be allocated to seminars on hot subjects and will be scheduled at a date closer to the event in order to ensure timeliness.

Key Words

DNA ,RNA, Chromosomes, Chromatin, Genetic Code, Gene Expression, Regulation, Proteins, Transcription, Replication, Duplication, Single Molecule, Biological Physics, Statistical Mechanics, Bioinformatics, Algorithms.

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The Lectures

Section 1: Biochemistry and Biology

(1) DNA: structure, dynamics and recognition by Richard Lavery
Introduction to the physical and biochemical structure of DNA/RNA molecules (microscopic structure, conformations, elementary vibrations) and to experimental characterization techniques (spectroscopy, NMR, neutron scattering, ...). The microscopic mechanisms underlying the treatment of genetic information (replication, transcription, ...) will be exposed.

(2) Gene and genome: organization and Regulation by Jim Kadonaga
Presentation of the different mechanisms for gene expression and regulation, both at the elementary level and at higher organization levels of DNA (chromatin). This lecture is of fundamental importance to understand the bioinformatics lectures of Section 3.

(3) RNA: from Sequence to Structure by Eric Westhof
Introduction to the RNA molecule, and related issues: dynamics of folding, structure prediction from sequence, ...

Section 2: Biophysics, from Experiments to Modelling and Theory

(4) Single Molecules: Experiments by Terence Strick
Recently developed techniques of micromanipulations allowing to study the properties of a single molecule of DNA or RNA, also in presence of proteins, will be reviewed. Results of these experiments will be presented and compared to usual biological bulk studies.

(5) Statistical physics of polymers and macromolecules by Alexei Khokhlov
Introduction to polymer physics and modelling, with emphasis on elasticity properties, coil-globule transition, and the influence of electrostatic interactions on macroscopic behaviour.

and Single Molecules: Modelling and Theory by John Marko
Presentation of statistical mechanics and polymer physics tools useful to interpret single molecule experiments
(elastic properties, structural transitions, ...). Approaches to the modelling of out-of-equilibrium processes e.g. DNA-protein interactions will also be exposed. 

(6) Physics of DNA electrophoresis by Tom Duke
Presentation of the electrophoresis characterization technique, of huge importance in molecular biology, and to the modelling of its action.

Section 3: Bioinformatics

(7) Regulatory sequence analysis by Jacques van Helden
Presentation of the main computational approaches for the discovery and the search of cis-regulatory patterns in nucleic acid sequences.

(8) Differential dynamical modelling of biological regulatory networks by Bela Novak
Introduction to the dynamical analysis of regulatory networks, with special emphasis on the use of the differential formalism and its application to the modelling of the eukaryotic cell cycle.

(9 )Dynamics of the Genome: evolution and repair by Francois Taddei
Introduction to the dynamical processes undergone by the genome. The course will be divided in five lectures, each illustrating an aspect of evolution and of some related open theoretical problem of interest to physicists.

Complementary lectures will be devoted to:
- Fluorescence correlation spectroscopy, by O. Krichevsky (Israel) in complement to lecture 4;
Theory of DNA thermal denaturation, by D. Mukamel (Israel) in complement to lecture 5;
- Reverse engineering of gene interactions on the basis of expression data, by D. Peer (Israel) in complement to lecture 8.
- Modelling and analysis of genetic networks structure and function, by M. Samsonova (Russia) in complement to lectures 7 and 8.

Additional seminars on hot subjects such as Atomic force microscopy for the visualisation of DNA under transcriptional regulation or replication, Matrix models for RNA folding, Patterns and structure of DNA, Dynamical modelling of genetic regulatory networks... will be scheduled depending on the progresses in the field in the next two years. They will take place during the first three weeks of the school.

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The Lecturers

Prof Richard Lavery (British, Institut Curie, Paris, France).

RL is the director of the Laboratoire de Biochimie Théorique. He has a long track record in the development of numerical methods for the modelling of Nucleic Acids and DNA-Protein Interaction.
He is a very clear lecturer on the subject as demonstrated .e.g. in the Single Molecule Biophysics, International EMBO Workshop, Tours (France) in 1999.
 

Dr Thomas Duke (British, Cavendish Lab, Cambridge, UK).
TD is a Royal Society Research Fellow. He is a young and versatile theoretician , who has largely contributed to the development of the theory of electrophoresis.

Prof Alexei Khokhlov (Russian, Moscow State University, Russia).
AK is head of the polymer physics laboratory at MSU, and a leader in the field of polymer and macromolecules theory. He has a very strong experience in teaching, and has written 6 books in the field.

Prof Jim Kadonaga (American, University of California at Los Angeles, USA).
JK has made important contributions to the study of chromatin and large scale organization of DNA. He is a very clear lecturer as demonstrated e.g. in the ASI summer school held in Corsica in 2000.
 

Prof Eric Westhof (French, Université Louis Pasteur (ULP), Strasbourg, France).
EW is a professor at ULP and is the head of the CNRS Laboratory Structure des macromolécules biologiques et mécanismes de reconnaissance. He has done fundamental works in RNA folding and structure predictions.

Prof Francois Taddei (French, Génétique Moléculaire évolutive et Médicale, Faculté de Médecine "Necker - Enfants Malades", Université René Descartes, Paris, France).
FT is a young biologist, specialist of the molecular mechanisms of evolution. He has realized important works on the adaptation, variability and diversity of bacteria.

Dr Terence Strick (American, Coldspring Harbor, USA).
TS is a young experimentalist, who did his Ph.D. in the Bensimon and Croquette lab in Paris.
He is at the leading edge of single molecule micromanipulation technique to study DNA and DNA-protein interactions. He is a very clear lecturer as demonstrated in several seminars.

Prof John Marko (American, Physics Department, University of Illinois at Chicago, USA).
JM is a theoretical physicist and, at the same time, head of an experimental lab. He was a pioneer in the modelling of elastic properties of DNA and single molecule experiments. He is also well known for the quality of his lectures and seminars.

Prof Jacques van Helden (Belgian, Université Libre de Bruxelles, Belgium).
JvH is particularly known for his work on the development of a very successful computer suite(RSA-tools) for the discovery and the search of cis-regulatory patterns in nucleic acids.

Prof Bela Novak (Hungarian, Technical University of Budapest, Hungary).
In close collaboration with John Tyson, BN has been developed dynamical models of the molecular networks controlling cell cycles in various eukaryotes for the last twenty years. His work is representative of the state of the art of biological dynamical modelling.

Dr Dana Peer (Israeli, The Hebrew University at Jerusalem, Israel)
DP is a young computer scientist, working on the analysis of gene expression data and genetic and regulatory networks reconstruction. She is an expert on machine learning and Bayesian methods.

Prof Oleg Krichevsky (Israeli, Beer-Sheva University, Israel).
OK is a physicist studying the interactions between and within biological molecules. He has been very successful in developing and implementing ultra-sensitive fluorescence microscopy techniques to allow real-time monitoring and conformational fluctuations of single biological molecules, such as DNA and proteins.

Prof David Mukamel (Israeli, Weizmann Institute, Israel).
DM is professor in the Department of Physics of Complex Systems at the Weizmann Institute. He has worked on many aspects of the statistical physics of disordered and out-of-equilibrium systems, with a special interest in applying sophisticated theoretical physics tools to the study of biophysical and biological systems.

Dr Maria Samsonova (Russian, Center of Advanced Studies, St.Petersburg Polytechnical University, Russia).
MS is heading the Department of Computational Biology at St Petersburg PU. Her current research interests covers the modelling and analysis of genetic networks structure and function, database design, the development of methods for quantification and analysis of in situ gene expression patterns, as well as text mining.

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Tentative schedule

Week 1

Week 2

Week 3

Week 4