Julien MOZZICONACCI, National Museum of Natural History - Paris

Nucleosomes, the fundamental units of DNA folding in eukaryotes, play critical roles in chromosome structure and gene regulation. Our research group, collaborating with experimental teams at the Pasteur Institute, investigates the sequence-based mechanisms that determine specific nucleosome positioning across genomes.

We developed a computational deep mutational screening approach to quantify how individual genetic mutations affect nucleosome positioning in Saccharomyces cerevisiae. The results can not only guide the design of modified yeast genomes but also provides insights into the sequence-dependent mechanisms of nucleosome positioning in living cells.

Our computational approach was then applied to yeast strains containing artificial bacterial chromosomes, demonstrating the predictive power of our model in characterizing chromatin structures across diverse genomic contexts.

We next proposed a new computational method integrating kinetic Monte Carlo modeling and deep learning predictions. This approach enables the rational design of novel DNA sequences with customized nucleosome periodicities in yeast. The engineered sequences can accommodate periodicities significantly larger than the natural yeast period, offering new opportunities to explore chromatin structure-function relationships.

Finally, we extended our methodology to mouse embryonic stem cells, identifying key sequence elements that drive nucleosome positioning. Our work reveals islands of regularly spaced nucleosomes around nucleosome positioning regions, uncovering the relationships between nucleosome positioning, transcription factor footprints and DNA repeats.

Genome-wide prediction of DNA mutation effect on nucleosome positions for yeast synthetic genomics. E Routhier, E Pierre, G Khodabandelou, J Mozziconacci Genome Research 31 (2), 317-326

Sequence-dependent activity and compartmentalization of foreign DNA in a eukaryotic nucleus. Meneu L, Chapard C, Serizay J, et al. SCIENCE 2025 doi: 10.1126/science.adm9466.

In silico design of DNA sequences for in vivo nucleosome positioning. E Routhier, et al. Nucleic Acids Research, gkae468

Contact : A. Piazza & D. Jost