9:20 - 10:00 

Seminar Isabel CHILLÓN - EMBL, Grenoble, FRANCE

“Molecular Mechanisms of Stress-Activated Long Non-Coding RNAs”

10:00 - 10:40

Seminar Bruno DI STEFANO - MGH - Harvard Medical School, Boston, USA

"Dissecting mechanisms that govern cellular plasticity"

11:00 - 11:40           

Seminar Teddy JÉGU - Harvard medical School, Boston, USA

"Characterization of epigenetic factors during pancreatic cancer progression"

11:40 - 12:20    

Seminar Kevin Stuart LANG - Vanderbilt University, Nashville, USA

"High-troughput genomics to study genome stability"

12:20 - 13:00         

Seminar Fabio PUDDU - Gurdon Institute - University of Cambride, Cambridge, UK

"Replication-transcription conflicts: the clash of the macromolecular titans"

Affiche du séminaire

The research focus of the lab is to understand the relevance of mitochondrial dynamics in health and disease.  The morphology of mitochondria is inextricably linked to its many essential functions in the cell and we are interested in understanding the relationship between mitochondrial shape changes and metabolism in the context of acquired and inborn human diseases.  I will discuss ongoing work using genetic screens to identify factors novel regulators and modulators of mitochondrial morphology in cells from patients with mitochondrial genetic diseases and the lessons we are learning regarding the importance of balanced mitochondrial dynamics.  I will also discuss the relevance of mitochondrial fission in cardiac metabolism and the connections between mitochondria, cell death, inflammation and heart failure in novel models developed by our lab.

Accurate DNA replication is essential for genomic stability and cancer prevention. Homologous recombination is important for high-fidelity DNA damage tolerance during replication. How the homologous recombination machinery is recruited to replication intermediates is unknown. We recently showed that a Rad51 paralog-containing complex, the budding yeast Shu complex, recognizes and enables tolerance of abasic sites during DNA replication predominantly on the lagging strand.  We performed whole genome sequencing in Shu complex mutants upon MMS exposure and uncovered a mutation signature consistent with accumulation of abasic sites and an additional lesion, 3-methylcytosines.  In bacteria and mammalian cells, the ALKB family of enzymes recognizes and repairs 3-methylcytosines.  However, budding yeast do not have an ALKB homolog.  Therefore, it remains unknown how 3-methycytosines are removed and repaired.  Here, we provide evidence that the yeast Shu complex has evolved to recognize and promote error-free bypass of 3-methylcytosines during DNA replication.  Preliminary data suggests that Shu complex function in error-free bypass of abasic sites and 3-methylcytosines is likely conserved in higher eukaryotes.

Dr. Jean-Pierre Quivy (Institut Curie UMR3664 – G. Almouzni team “Chromatin Dynamics”) will present an ongoing project in which a marker of centromeric chromatin was found to be highly predictive for response to radio-chemotherapy in head and neck cancer.

To be confirmed: Dr. Leticia Niborski (Institut Curie U932 – E. Piaggio team “Translational Immunotherapy”) will present her work on heterochromatin factors, lineage commitment and T cell differentiation.

Any cell population growing in confinement can experience a growth-induced compressive stress, from bacteria to animal cells. We observe in the budding yeast S. cerevisiae that growth decreases under pressure, and that this decrease does not seem to depend on specific mechanosensors. Using novel genetically-encoded nanoparticles (GEMs) to assess the rheological properties of a cell, we show that compressive stress alters the motion of macromolecules inside the cell, in a size-specific manner. Under compression, reactions such as protein synthesis become diffusion-limited, globally decreasing the dynamics of biomass production. We will in the end explore the possibility that the cytosolic rheological properties are partly conserved across organisms, expanding the observations on S. cerevisiae to other organisms such as bacterial and mammalian cells.

Drug resistance dissemination by horizontal gene transfer remains poorly understood at the cellular scale. Using live-cell microscopy, we reveal the dynamics of resistance acquisition by transfer of the F conjugative plasmid encoding the tetracycline-efflux pump TetA. We show that the entry of the ssDNA plasmid into the recipient cell is rapidly followed by complementary strand synthesis and expression of newly acquired genes. TetA production is enhanced by zygotic induction resulting in the optimized establishment of resistance. In the presence of protein synthesis-inhibiting antibiotics, acquisition of resistance becomes strictly dependent on AcrAB-TolC multidrug efflux pump. We demonstrate that AcrAB-TolC is required for maintenance of protein synthesis activity and therefore TetA production following plasmid acquisition. This work uncovers a novel essential role of multidrug efflux systems in the acquisition of drug-specific resistance by horizontal gene transfer and helps to understand the dissemination of antibiotic resistance in bacteria.

In human cells, two meters of DNA sequence are compressed into a nucleus whose linear size is five orders of magnitude smaller. Deciphering how this amazing structural organization is achieved and how DNA functions can ensue in the environment of a cell’s nucleus represent central questions for contemporary biology.

Here, I embrace this challenge by establishing a comprehensive framework of microscopy and sequencing technologies coupled with advanced analytical approaches, aimed at addressing three fundamental highly-interconnected questions: 1) What are the design principles that govern DNA compaction? 2) How does genome structure vary between different cell types as well as among cells of the same type? 3) What is the link between genome structure and function? To this aim, we have devised a powerful method for Genomic loci Positioning by Sequencing (GPSeq), which allows genome-wide measurements of the distance of genomic loci to the nuclear periphery. Using GPSeq, we are generating reproducible maps of radial genome organization in human cells, in order to reveal radial gradients of genetic and epigenetic features as well as gene expression in various cell and tissue types. In parallel, we are developing high-end microscopy tools for simultaneous localization of dozens of genomic locations at high resolution in thousands of single cells.