ERC FUNDED PROJECTS

Homologous recombination (HR) is a conserved DNA double-strand breaks (DSB) repair pathway that uniquely uses an intact DNA molecule as a template. Genome-wide homology search is carried out by a nucleoprotein filament (NPF) assembled on the ssDNA flanking the DSB, and whose product is a “D-loop” joint molecule. Beyond accurate DSB repair, this capacity of HR to spatially associates homologous molecules is also harnessed for homolog pairing in meiosis. The goal of “3D-loop” is to tackle two long lasting conundrums: the fundamental homology search mechanism that achieves accurate and efficient identification of a single homologous donor in the vastness of the genome and nucleus, and how this mechanism is adapted for the purpose of homologs attachment in meiosis. I overcame the main hurdle to study these core steps of HR by developing a suite of proximity ligation-based methodologies and experimental systems to physically detect joint molecules in yeast cells. It revealed elaborate regulation controlling D-loop dynamics and a novel class of joint molecules. This proposal builds upon these methodologies and findings to first address basic properties of the homology sampling process by the NPF and the role of D-loop dynamics, with the long-term goal to establish a quantitative framework of homology search in mitotic cells (WP1). Second, the meiosis-specific regulation of homology search leading to homolog pairing likely integrates chromosomal-scale information. Genome re-synthesis and engineering approaches will be deployed to (i) achieve a quantitative and dynamic cartography of the cytological and molecular events of meiosis over a large chromosomal region, (ii) probe cis-acting regulations at the chromosomal scale, and (iii) revisit the molecular paradigm for crossover formation (WP2). We expect this project to shed light on the fundamental process of homology search and its involvement in the chromosome pairing phenomenon lying at the basis of sexual reproduction.

1 499 779 €

Start date: 2020-01-01, End date: 2024-12-31

This project investigates the two-way relationship between spatio-temporal genome organization and coordinated gene regulation, through an approach at the interface between physics, computer science and biology. In the nucleus, preferred positions are observed from chromosomes to single genes, in relation to normal and pathological cellular states. Evidence indicates a complex spatio-temporal coupling between co-regulated genes: e.g. certain genes cluster spatially when responding to similar factors and transcriptional noise patterns suggest domain-wide mechanisms. Yet, no individual experiment allows probing transcriptional coordination in 4 dimensions (FISH, live locus tracking, Hi-C...). Interpreting such data also critically requires theory (stochastic processes, statistical physics…). A lack of appropriate experimental/analytical approaches is impairing our understanding of the 4D genome. Our proposal combines cutting-edge single-molecule imaging, signal-theory data analysis and physical modeling to study how genes coordinate in space and time in a single nucleus. Our objectives are to understand (a) competition/recycling of shared resources between genes within subnuclear compartments, (b) how enhancers communicate with genes domain-wide, and (c) the role of local conformational dynamics and supercoiling in gene co-regulation. Our organizing hypothesis is that, by acting on their microenvironment, genes shape their co-expression with other genes. Building upon my expertise, we will use dual-color MS2/PP7 RNA labeling to visualize for the first time transcription and motion of pairs of hormone-responsive genes in real time. With our innovative signal analysis tools, we will extract spatio-temporal signatures of underlying processes, which we will investigate with stochastic modeling and validate through experimental perturbations. We expect to uncover how the functional organization of the linear genome relates to its physical properties and dynamics in 4D.

1 499 750 €

Start date: 2018-04-01, End date: 2023-03-31

Listening in realistic situations is an active process that engages perceptual and cognitive faculties, endowing speech with meaning, music with joy, and environmental sounds with emotion. Through hearing, humans and other animals navigate complex acoustic scenes, separate sound mixtures, and assess their behavioral relevance. These remarkable feats are currently beyond our understanding and exceed the capabilities of the most sophisticated audio engineering systems. The goal of the proposed research is to investigate experimentally a novel view of hearing, where active hearing emerges from a deep interplay between adaptive sensory processes and goal-directed cognition. Specifically, we shall explore the postulate that versatile perception is mediated by rapid-plasticity at the neuronal level. At the conjunction of sensory and cognitive processing, rapid-plasticity pervades all levels of auditory system, from the cochlea up to the auditory and prefrontal cortices. Exploiting fundamental statistical regularities of acoustics, it is what allows humans and other animal to deal so successfully with natural acoustic scenes where artificial systems fail. The project builds on the internationally recognized leadership of the PI in the fields of physiology and computational modeling, combined with the expertise of the Co-Investigator in psychophysics. Building on these highly complementary fields and several technical innovations, we hope to promote a novel view of auditory perception and cognition. We aim also to contribute significantly to translational research in the domain of signal processing for clinical hearing aids, given that many current limitations are not technological but rather conceptual. The project will finally result in the creation of laboratory facilities and an intellectual network unique in France and rare in all of Europe, combining cognitive, neural, and computational approaches to auditory neuroscience.

3 199 078 €

Start date: 2012-10-01, End date: 2018-09-30

In the road towards quantum technologies capable of exploiting the revolutionary potential of quantum theory for information technology, a major bottleneck is the large overhead needed to correct errors caused by unwanted noise. Despite important research activity and great progress in designing better error correcting codes and fault-tolerant schemes, the fundamental limits of communication/computation over a quantum noisy medium are far from being understood. In fact, no satisfactory quantum analogue of Shannon’s celebrated noisy coding theorem is known. The objective of this project is to leverage tools from mathematical optimization in order to build an algorithmic theory of optimal information processing that would go beyond the statistical approach pioneered by Shannon. Our goal will be to establish efficient algorithms that determine optimal methods for achieving a given task, rather than only characterizing the best achievable rates in the asymptotic limit in terms of entropic expressions. This approach will address three limitations — that are particularly severe in the quantum context — faced by the statistical approach: the non-additivity of entropic expressions, the asymptotic nature of the theory and the independence assumption. Our aim is to develop efficient algorithms that take as input a description of a noise model and output a near-optimal method for reliable communication under this model. For example, our algorithms will answer: how many logical qubits can be reliably stored using 100 physical qubits that undergo depolarizing noise with parameter 5%? We will also develop generic and efficient decoding algorithms for quantum error correcting codes. These algorithms will have direct applications to the development of quantum technologies. Moreover, we will establish methods to compute the relevant uncertainty of large structured systems and apply them to obtain tight and non-asymptotic security bounds for (quantum) cryptographic protocols.

1 492 733 €

Start date: 2021-01-01, End date: 2025-12-31