Elucidating molecular organization and protein functions requires localizing precisely single or aggregated molecules and analyzing their spatial distributions. We develop a statistical method SODA (Statistical Object Distance Analysis) that uses either micro- or nanoscopy to significantly improve standard co-localization techniques (Lagache et al, Nature Comm 2018). Our method considers cellular geometry and densities of molecules to provide statistical maps of isolated and associated (coupled) molecules. SODA can be used with three-color structured-illumination microscopy (SIM) images to statistically characterize spatial organization of thousands of protein clusters or vesicles. As this methods do not rely on physical overlaps, SODA can be used to detect indirect molecular association in conventional microscopy or even in super resolution microscopy where higher resolution prevent the use of conventional overlay methods.

To reconstitute molecular maps within cellular shape, we recently developed new membrane probes call the MemBright family (on the cover of Cell Chemical Biololgy, April 2019). MemBright is a family of six cyanine based fluorescent turn-on PM probes that emit from orange to near infrared when reaching the PM, and enable homogeneous and selective PM staining with excellent contrast in mono- and two-photon microscopy. These probes are compatible with long-term live-cell imaging and immunostaining both in cultures cells and tissue without any use of transfection or transgenic animals. MemBright probes can be used in super-resolution imaging to unravel the plasma membrane structures like the tiny dendritic spines protrusions. 3D multicolor dSTORM in combination with immunostaining can be used to labels receptors clustered at cell surface and to decipher molecular organization at single molecule level. This presentation will illustrate through various cell biology questions how MemBright probes constitute a universal toolkit for cell biology and neuroscience biomembrane imaging with a variety of microscopy techniques.

Chemistry opens many possibilities to develop new tools to understand the biology and discover new treatments for human diseases. The development of chemical reactions that occur in living systems has been a breakthrough for biology and medicine and has enabled to observe and study biomolecules in living systems with excellent biocompatibility. Chemical probes can reveal the function of a specific biomolecule in the biological context. Thus, they constitute a valuable toolbox for in detail studies of the biological processes. We develop chemical probes to target epigenetic modifications, in particular DNA and histone methylation. Our goal is to modulate gene expression in cells. Currently there is a large interest in the role of epigenetic changes in human diseases and great expectations from drugs bridling these changes1. Proteins involved in “writing”, “erasing” and “reading” of the chemical chromatin modifications conveying the epigenetic regulation have been identified and studied. Some inhibitors have been designed and are in clinical trials for cancer. Recently it has emerged that these modifications play a major role also in other diseases2. I will show examples of the design of compounds that modulate the methyltransferases of DNA3 and histones4, discuss their advantages and limits compared to biological tools5. These compounds are able to impact the cancer phenotype6, but they also open new avenues to fight antimicrobial resistance and in particular in malaria7.

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Dr. Paola Arimondo (Institut Pasteur) works at the interface of Chemistry and Biology to design new chemical molecules targeting DNA and histone methylation. These new molecules are used to better understand the molecular processes that deregulate these modifications in cancer and constitute potential therapeutic agents to reprogram gene regulation in cancer cells.

Dr Yuna Blum (CIT Program, French League Against Cancer) is an expert in (epi)genetic data analyses. Her presentation will focus on the heterogeneity of DNA methylation and histone marks, both among pancreatic cancer patients and within one tumor using signal deconvolution tools.

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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. 

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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. 

Hematopoietic Stem Cells (HSCs) at the origin of blood and immune cells are born during a narrow time window of the vertebrate embryonic development. HSC​s precursor cells originate from blood vessels and in particular the ventral floor of the dorsal aorta. They do so according to a process referred to as the Endothelial-to H​ematopoietic Tra​nsition (EHT) in which a subset of aortic cells, committed to enter a specific genetic program - in part controlled by the mechanical forces resulting from the blood flow -,extrude from the vascular wall. This extrusion process is relatively unique, partly owed to the biophysical conditions imposed by hemodynamic forces and also to the organization of the thin endothelial layer.
We have recently characterized the EHT process using the zebrafish embryo that offers unique advantage​s among which the relative easiness to perform live-imaging at high spatiotemporal r​esolution. We have shown that the EHT involves unusual cellular morphodynamics,​ with inward bending of both apical/luminal and basal membranes toward the sub-aortic space​, anisotropic contraction of the cell apex contacting adjoining endothelial cells (supported by contractile circumferential actomyosin) and anisotropic organization of junctional complexes reinforced at antero-posterio​r poles (organized according to an axis that aligns with blood flow). Even more recently (unpublished work), we found that HSC precursor scan extrude via another type of emergence that does not involve cellular bending and that appears to require specific intercellular adhesion remodeling. 
​In this seminar, I will describe the specificities of the two types of EHT, including a model of differential adhesion remodeling (2D- versus 3D-displacement modes) and discuss the possibility of an impact of the mechanistic principles of EHT cell emergence on downstream cell fate.

Séminaire proposé par Giulia CARZEDDA

Cellular senescence is a complex and dynamic cellular program, with multiple functions throughout life. Primarily, senescence is a form of irreversible cell cycle arrest induced inresponse to a variety of stressful stimuli, including aging, DNA-damage and oncogenic stimulation. As such, senescence acts as a tumor suppressive or protective mechanism, to
limit the aberrant proliferation of damaged or potentially oncogenic cells. In addition, senescent cells accumulate chronically during aging, where they actively contribute to the aging process and to age-associated disease pathogenesis. Interestingly, recent advances in the field have identified how the elimination of senescent cells with genetic or pharmacological means, can have beneficial effects in aged and diseased states. However, work from our group and others has identified how transiently-present senescent cells can have beneficial effects in situations including embryonic development, tissue regeneration and reprogramming.

Our lab is interested in further exploring the dynamic cellular program of senescence, its varied biological functions in development and disease, and how it is properly controlled. Here, I will summarize our previous studies describing senescence during normal embryonic development and tissue regeneration. In addition, I will discuss new findings implicating aberrant senescence in developmental birth defects, and investigating how the dynamic cellular program of senescence may contribute to disease and aging.

Assistant Professor, Department of Genetics

University of Georgia

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