During vertebrate development, Hox genes follow a time sequence in their transcriptional activation, which progresses in cis along their respective genomic clusters. While the importance of this ‘Hox clock’ to secure and coordinate body patterning has been recognized, the underlying mechanism are still elusive. We have designed and used genetic approaches to produce large allelic series in mice, including deletions, duplications and inversions at the HoxD locus, to try and understand the relationship between gene topography and transcriptional onset.

By using ChIP and Chromosome Configuration Capture on micro-dissected embryonic material, we show that successive Hox gene activation in the embryo is closely associated with both a directional transition in chromatin status, as judged by the dynamic replacement of repressive marks by transcription-competent modifications, and a spatial re-organisation of the locus, suggesting that the Hox clock may be regulated by an epigenetic mechanism, leading to the progressive accessibility of Hox clusters to the transcription machinery (open for business). I will discuss both the impact, in term of ontogenetic and phylogenetic constraint, of such a cis-acting regulatory system upon the stability of the animal body plan, and its potential to produce morphological flexibility via heterochronic modifications, as exemplified with some vertebrate species.

Elizabeth Blackburn

University of California, US

Elizabeth Blackburn is a leader in the area of telomere and telomerase research. She discovered the molecular nature of telomeres-the ends of eukaryotic chromosomes that serve as protective caps essential for preserving the genetic information - and discovered the enzyme telomerase, which replenishes telomeres. Blackburn is currently the Morris Herzstein Endowed Professor in Biology and Physiology in the Department of Biochemistry and Biophysics at University of California, San Francisco, where she is working with various cells including human cells, with the goal of understanding telomerase and telomere biology. She is also a Non-Resident Fellow of the Salk Institute. Throughout her career, Blackburn has been honored by her peers as the recipient of many prestigious awards, including The Albert Lasker Medical Research Award in Basic Medical Research (2006), and she was selected as the 2008 North American Laureate for L'Oreal-UNESCO For Women in Science. In 2007 she was named one of TIME Magazine's 100 Most influential People. Winner of The Nobel Prize for Physiology or Medicine 2009.

Michel Haïssaguerre

University Victor-Segalen
Bordeaux, FR

Title & synopsis
Origin & treatment of atrial & ventricular fibrillation

Atrial and ventricular fibrillation are the most complex pathologies relating to cardiac rhythm. The former is the main cause of embolic cerebral vascular accidents. As for the latter, it is behind most cases of sudden death in adults, affecting 350’000 people every year in Europe. First of all, Michel Haïssaguerre studied the genesis of atrial fibrillation. In creating a «heart map» he was the first to notice that the electrical problems causing the illness were not occurring in the atrium, as had been thought for a long time, but further upstream in the cells situated in external wall of the pulmonary veins. This discovery was confirmed by numerous clinics across the world, and led to the development of a new treatment involving the ablation by cryotherapy or ultrasound of the cells causing atrial fibrillation. In 2009, 150'000 persons received this treatment, and the number of cases thus managed is growing constantly.
Michel Haïssaguerre and his team adopted this same original approach to look into the causes of ventricular fibrillation. Although in this case the heart mapping technique was more difficult due to the instantaneous nature of the disorder, which calls for immediate defibrillation using electric shocks, they achieved their goal. They demonstrated that these «electrical tornados» emanate from the tissue known as «de Purkinje», which only accounts for the tiniest fraction (2%) of the cardiac mass. The concept has since been validated in clinical trials on a few patients. Thermoablation focused on this tissue totally eliminated these patients' arrythmias.

Title & synopsis
Design principles of pluripotency

Pluripotency is the capacity of an individual cell to initiate formation of all lineages of the mature organism plus the germline directed by extrinsic cues from the embryo. A pluripotent cell is a blank slate with no predetermined programme. In mice and rats this naïve state at the foundation of mammalian development can be captured in culture. Self-renewing embryonic stem (ES) cells are isolated by suppressing differentiation triggers. fibroblast growth factor activation of the, which is the trigger for differentiation. This can be efficiently achieved using selective small molecule inhibitors of the fibroblast growth factor/ extracellular signal regulated kinase (Erk) cascade and of glycogen synthase kinase-3 (Gsk3). The cytokine LIF also supports both the derivation and propagation of ES cells and molecular reprogramming through activation of Stat3. We are investigating how Erk antagonism, Gsk3 inhibition and Stat3 activation contribute to creating, maintaining and recreating authentic pluripotency.