DNA replication follows a strict spatiotemporal program with a poorly understood genetic and epigenetic basis. To systematically uncover the genetic components of DNA replication timing regulation, we exploit inter-individual replication timing variation across human cells lines. In this talk, I will mainly describe our analysis of 116 human embryonic stem cell lines. By comparing replication timing variation to genetic polymorphisms, we identified 608 cis-acting replication timing quantitative trait loci (rtQTLs) – base-pair-resolution determinants of DNA replication timing. We show that rtQTLs function individually, or in combinations of proximal and distal regulators, to affect replication initiation activity. We reveal two layers of replication timing control: a histone code for replication initiation, composed of histone H3 trimethylations together with general histone hyperacetylation; and a multi-component layer that combinatorically fine-tunes DNA replication timing. The latter includes active histone marks and pluripotency-related transcription factors that promote early replication, and, conversely, chromosome topology boundary factors that repress replication when bound to DNA. Human replication timing is robustly encoded in DNA sequence and follows principles analogous to transcriptional regulation: a histone code, activators and repressors, and a promoter-enhancer logic.

Séminaire proposé par Nathalie Boissière,
Responsable de la Communication interne

Pour la 5e fois, nous vous proposons de nous retrouver pour la réunion semestrielle de l’ensemble des collaborateurs du Siège qui se déroulera mardi 17 décembre 2019 de 9h30 à 14h dans le Bâtiment biologie du développement et cancer (Campus Curie) 11/13 rue Pierre-et-Marie-Curie.

Si vous souhaitez faire parvenir en amont de la réunion une question sur l’un des points à l’ordre du jour ou tout autre sujet, merci de l’envoyer à communication.interne@curie.fr  d'ici mardi 3 décembre midi.

Liquid biopsy has the potential to revolutionize the clinical management of cancer patients and improve disease outcome. In this framework, circulating tumor cells (CTCs) could increase the temporal and spatial representativeness of heterogeneous solid tumors, both in primary and metastatic sites. We introduce novel micro-engineered devices for the isolation of CTCs from whole blood based on their intrinsic physical properties. Our technological solution, relying on cutting-edge microfabrication technologies supported by advanced computational simulations, was conceived to meet clinical requirements in order to allow the isolation of a large number of CTCs with low contamination levels, under physiological flow conditions (low-pressure regimes) and no blood pre-processing required to preserve cellular integrity and provide high-quality information. Captured cells can then be easily characterized, or collected for downstream analysis. The versatility and portability of our solution renders it compatible with clinical routine, a step forward towards the implementation of liquid biopsy in clinical settings to guide medical decisions, monitor disease and adapt treatment plans at the patient scale.

In this talk, I will tell about an emerging topic of the clinical trial design – adaptive designs. We will introduce what the adaptive design is, and consider its one of the most common variants – multi-arm multi-stage (MAMS) design, in which several treatments are compared to the common control. We will discuss the construction of the design and the sample size calculation ensuring that type I and type II errors are controlled.

In many MAMS trials, however, the fixed equal randomization of patients is used. Motivated by ethical concerns, we will then consider an developing class of adaptive designs allowing for the skewed allocation of patients towards the most effective treatments – the response-adaptive designs. Specifically, we will consider the multi-arm bandits model as one of the response-adaptive designs. We introduce a newly developed response-adaptive design which is based on recent advanced in information-theory and compare its performance with the standard (non-adaptive) approach and the multi-arm bandit design.

___

L’oreille humaine est un capteur fascinant, capable de détecter un éventail de sons couvrant dix octaves en fréquence et douze ordres de grandeur en amplitude. Ces propriétés exceptionnelles résultent de phénomènes non-linéaires qui se produisent au sein de la cochlée ; l’organe de l’oreille interne responsable de la conversion des stimuli sonores en impulsions nerveuses qui parviennent ensuite à notre cerveau. La compréhension de tels mécanismes constitue à la fois un enjeu fondamental mais également une opportunité pour améliorer les performances des microphones, qui sont encore bien loin d’égaler celles de l’oreille humaine.

Dans un article publié dans New Journal of Physics [1], nous transposons des résultats obtenus récemment dans le domaine des « métamatériaux » acoustiques [2] au contexte de l’audition. À l’aide d’un dispositif constitué d’une succession de tubes résonants de hauteurs croissantes (figure 1), nous avons reproduit expérimentalement un analogue de la réponse cochléaire. La fréquence de résonance d’un tube étant pilotée par sa hauteur, chacun d’entre eux sélectionne une note bien précise, permettant de dissocier spatialement les composantes fréquentielles d’un signal. Ce phénomène, appelé sélection tonotopique, a pu être observé sur des cochlées ex-vivo.

Mais ce qui est fascinant dans la biologie de la cochlée, c’est justement son caractère vivant et sa capacité à influer de manière active sur sa propre réponse. Ainsi, la cochlée se comporte différemment selon qu’elle est excitée par des sons faibles ou intenses. C’est cette dite amplification cochléaire qui nous permet d’entendre les sons les plus ténus. Pour imiter cette propriété, nous avons en quelque sorte animé les tubes de notre métamatériau, en les dotant d’un phénomène actif par l’ajout d’une boucle de rétroaction. Pour cela, un haut-parleur placé à l’extrémité de chaque tube émet en temps réel un son qui est directement relié au son enregistré par un microphone placé dans ce même tube. Les résultats montrent que notre cochlée artificielle reproduit qualitativement le comportement d’une cochlée biologique. Cela nous ouvre de nouveaux horizons à explorer expérimentalement à une échelle macroscopique dans la biophysique de la cochlée, avec notamment des perspectives intéressantes dans le traitement de la surdité ou bien dans la compréhension de phénomènes tels que les fréquences fantômes de Tartini ou encore l’oto-émission.

Affiche du séminaire

Meiotic maturation is the final step of oogenesis when oocytes undergo two cell divisions without DNA replication to become haploid eggs. During this transition, de-novo accumulation of proteins and degradation of maternal mRNAs support progression through meiosis and render the egg competent for the embryo development. Our projects characterize the switch in the translation landscape that occurs during meiosis at a genome-wide level. Important components of the cell division machinery are regulated in this manner, as Cyclins B1 and B2, two activators of Cdk1, the master regulator of mitosis and meiosis. Overall, our results reveal the bidirectional regulation between the translation program and cell divisions.

The advances in high-throughput and single-cell technologies in biomedical research are generating an unprecedent amount of data that needs to be analyzed and integrated into their biological context. The team of Maria Rodríguez Martínez develops machine and deep-learning tools, together with statistical and mathematical modelling to explore multi-omics and single-cell proteomics datasets of tumor samples.

Maria’s team has recently developed AI algorithms to analyze breast cancer cellular heterogeneity at the proteomic level, and this way contribute to dissect the molecular mechanisms of cancer, and develop predictive models of disease progression and treatment.

This seminar is part of the LifeTime initiative and the Nuclear Dynamics series

Here you can find their publications

Affiche du séminaire

Affiche du séminaire

Dr. Nelson is a native of Vancouver BC. He received his B.Sc. from the University of British Columbia in 1987 and Ph.D. from the University of California at Berkeley in 1991. He completed postdoctoral training with Dr. Phil Greenberg and held faculty positions at the Fred Hutchinson Cancer Research Center and University of Washington in Seattle. In 2003, he became the founding Director of BC Cancer's Deeley Research Centre in Victoria BC. He is a Professor of Medical Genetics at the University of British Columbia and a Professor of Biochemistry/Microbiology at the University of Victoria. Dr. Nelson’s lab uses genomic and molecular approaches to study the immune response to cancer, with an emphasis on ovarian cancer. As Co-Director of BC Cancer’s Immunotherapy Program, he is leading a phase I clinical trials program focused on adoptive T cell therapy for gynecological cancers, leukemia, lymphoma, and other malignancies. 

Assistant Professor, Department of Genetics

University of Georgia

Affiche du séminaire