The folding of chromosomes is a carefully regulated process, essential to the function and propagation of DNA molecule(s) over generations. Past and recent work have revealed its importance in bacteria or eukaryotes, where regulatory mechanisms have evolved to coordinate chromosome organization with other DNA-related metabolic processes such as segregation. Our research is focusing on the interplay between chromosome dynamics, cell cycle, and consequences on chromosome stability. We work on three main research topics related to chromosome folding, through a combination of genome-wide and single-cell technologies (3C, Hi-C, imaging), synthetic methods (neo-chromosome assembly), as well as in vitro and in vivo approaches.
- First, we investigate the functional organization of chromosomes in a variety of model microorganisms, including pathogens.
- Second, we develop and apply new genomic techniques exploiting chromosome 3D contacts to investigate complex microbial communities.
- Finally, we investigate infection from the point of view of chromosome structure, to improve our understanding of these processes.
Among our recent results, we are reaching at a better understanding of the organizational changes experienced by yeast and bacterial genomes during replication and cell cycle, and how it is being influenced by metabolism (e.g. Lioy et al., 2018; Lazar-Stefanita et al., 2017; Marbouty et al., 2015; Guidi et al., 2015). We pursue our investigation of yeast synthetic chromosomes in collaboration with the Sc2.0 project coordinated by Jef Boeke (NYU) (Mercy et al., 2017), while developing our own synthetic chromosomes in yeast to address questions related to homolog pairing (Muller et al., 2018).
While studying the biology of genome folding with combination of experimental and computational approaches, we concomitantly developed computational techniques aiming at improving genome assembly and metagenomic/pan-genomic analysis through the exploitation of chromosome physical 3D signatures (Marbouty et al., 2014, 2017; Marie-Nelly et al., 2014a, 2014b). These “proximity ligation” approaches have opened up new areas of research, which holds potential for both fundamental discoveries and biomedical applications (Flot et al., 2015; Marbouty and Koszul, 2015). Performed over time, these approaches allows tracking the propagation of genes or genetic elements of interest throughout a complex ecosystem. We published some of the first programs and pipelines to scaffold incomplete genomes using Hi-C data (GRAAL, instaGRAAL), bin metagenomes using Hi-C (metaTOR), all available on github https://github.com/koszullab/.
Digging computationally in the DNA contacts between molecules belonging to different species led us towards questions related to viral infection, and more specifically how a DNA virus infiltrates the higher order architecture of a prokaryotic or eukaryotic host. In collaboration with Christine Neuveut, we recently showed that hepatitis B virus (HBV) preferentially contacts active chromatin in human hepatocytes at CpG islands (CGIs) (Moreau et al., 2018). Cfp1, a transcription factor at CGIs is required for HBV transcription and is recruited on the viral molecule, suggesting that HBV preferentially contacts regions that are enriched in factors important for its own transcription. We are now pursuing this line of research to characterize the mechanisms responsible for the relocation of the virus, as well as other aspects of HBV metabolisms.
Our ongoing research projects include regulation of cohesin-dependant folding of yeast and bacterial chromosomes during the cell cycle ; The influence of transcription on chromosome organization in those species ; and influence of chromatin organization of meiotic double-strand break repair and mitotic genome stability. We are also pursuing the development of contact genomic applications, that we are now applying to a broad variety of questions, including metagenomic analysis, gene flow, etc. Finally, we are trying to understand how large, host genomes cope with infection processes, and whether changes in their 3D organization can inform us about some molecular mechanisms at play.
Our projects usually involve collaborative efforts between geneticists, biophysicists and mathematicians, some in the lab and some through collaborations. The lab therefore welcome all kind of applications by students or postdocs interested to join!
Check out our Github space for code and programs