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3 funded positions available in Montpellier for a PhD training network on
Role of phase separation mechanisms in higher-order chromatin organization during development

Marcelo Nollmann (Centre of Structural Biochemistry – CBS) -
Giacomo Cavalli (Institute of Human Genetics – IGH) -
Andrea Parmeggiani (Laboratoire Charles Coulomb – L2C) -

Project Abstract

Polycomb group (PcG) proteins silence master regulatory genes required to properly confer cell identity during development in both Drosophila and mammals, and they do so by mediating the formation of H3K27me3 chromatin domains. PcG proteins compact chromatin and form higher-order hubs inside the cell nucleus, but the molecular mechanisms at the basis of PcG-dependent 3D chromatin folding are poorly understood. The cell nucleus is a highly organized yet dynamic organelle. Besides chromosomes, it contains a variety of membrane-less compartments, including nuclear bodies (i.e. nucleolus, P-bodies, etc) assembling through liquid-liquid Phase Separation (LLPS). LLPS is the process by which macromolecules separate, or demix, from the surrounding nucleoplasm to form distinct, coexisting liquid phases with different molecular compositions and material properties. Critically, condensation and higher-order folding of H3K27me3 chromatin domains in the nucleus need to be modulated between tissues in concordance with specific transcriptional programs. Recent models have suggested that phase separation may play a role in these processes. This PhD Training network will investigate the biological and physical mechanisms involved in the establishment and regulation of H3K27me3 domains and their relation with the process of phase separation. Students will get a highly interdisciplinary training in imaging-based genomics, epigenetics, advanced microscopies, and physical modeling. Their training will be enhanced by frequent rotations between labs, and participation in weekly, monthly, and annual network meetings to discuss results, exchange ideas, and improve presentation skills.
Keywords: 3D Genome Architecture, Single Cell Epigenetics, Imaging-based Genomics, Physical Modeling.


We encourage brilliant, highly motivated candidates with mastery of molecular biology, genomics and biophysics, fluent in English and willing to join a highly interdisciplinary scientific journey to apply via the website:

Funding is provided for 3 years. Deadline for application: May 25th, 2020

Fellowship 1

Multi-scale organization of H3K27me3 domains in single cells with spatial resolution

Dissection of single-cell heterogeneity in the condensation and higher-order organization of H3K27me3 domains and maintenance of spatial information are critical to understand and model the mechanisms of formation of H3K27me3 domains. Up until now, the lack of appropriate technologies impeded these measurements. The Nollmann lab has recently developed a novel imaging technique called Hi-M, based on the sequential hybridization, imaging and bleaching of Oligopaint FISH and RNA probes. This new technology enables: (1) the simultaneous detection of tens (25-100) of DNA loci in each single cell; (2) the reconstruction of chromatin architecture in single cells in whole-mount embryos while maintaining spatial information; (3) single-cell multi-omics, as it simultaneously measures 3D chromatin architecture and transcriptional status. We will use Hi-M to understand and characterize tissue specific and single cell variability in the higher-order folding organization of H3K27me3 domains. For this, we will further develop different technological aspects of HiM. These experiments will directly feed modelling efforts from the Parmeggiani Lab, and predictions from their models will be tested using our experimental methods. Hi-M experiments in Polycomb group mutants will be performed to understand the mechanism of folding of H3K27me3 domains, while Hi-C experiments in the Cavalli Lab will be done to get genome-wide information.
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Fellowship 2

Functional dissection of mechanisms involved in the formation of H3K27me3 domains

The Cavalli lab goal is to show whether Drosophila PcG proteins undergo liquid-liquid phase transitions and, if yes, identify the mechanism and consequences. To test this hypothesis, we will compare the nuclear distribution of different PcG proteins by observing immuno-labelling in confocal and super-resolution microscopy. We will perform co-localization experiments with the two histone marks H3K27me3 and H2A118Ub. The effect of PcG proteins on target genes will be monitored during embryogenesis by performing RNA FISH in both WT and mutant embryos. ChIP experiments will identify the genomic localization of PcG proteins during Drosophila embryogenesis and, we will analyze the effect of mutations on the genomic distribution of other PcG proteins and histone marks. We will use STED microscopy and Hi-M to analyze high-resolution chromosome folding to test the LLPS hypothesis. Wild type or mutated forms of PcG proteins will be overexpressed and their consequence on chromosome architecture and gene expression analyzed. These results will be used to feed modelling approaches from the Parmeggiani Lab. We will work with the Nollmann Lab to perform Hi-M analysis (see Project 1) in different genomic regions with genes either active or silenced by PcG proteins.
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Fellowship 3

Modelling the multi-scale organization of H3K27me3 domains

The Parmeggiani lab is specialized in theoretical physics modeling of complex systems and non-linear phenomena, in particular those inspired by biological systems, such as DNA and chromatin structures, membranes and complex biological transport phenomena such as cytoskeletal based intracellular transport and ribosome collective dynamics on RNA. Numerical and analytical methods are developed using non-linear physics, statistical mechanics, polymer physics and advanced methods in mathematical physics, which can be used for analytical modeling of protein dynamics and in silico experiments. The multi-scale organization of H3K27me3 domains and its regulation is key to understand epigenetic mechanisms and provides an excellent model-system to advance our knowledge of phase separation phenomena combining modeling with experimental data from single-cell microscopy and high-throughput analysis such as ChIP, HiM and Hi-C experiments. Our aim in this project is to provide a general theoretical view of the multi-scale organization and maintenance of H3K27me3 domains in close collaboration with the Nollmann and Cavalli Labs. The PhD student will work in our Lab on analytical and numerical models issued from polymer physics and the statistical mechanics of lattice gases in polymeric networks.
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