Exogenous chromosomes reveal how sequence composition drives chromatin assembly, activity, folding and compartmentalization

Genomic sequences co-evolve with DNA-associated proteins to ensure the orderly folding of long DNA molecules into functional chromosomes. In eukaryotes, this multiscale folding involves several molecular complexes and structures, ranging from nucleosomes to large cohesin-mediated DNA loops. To directly explore the causal relationships between the DNA sequence composition and the spontaneous loading and activity of these complexes in the absence of co-evolution, we used and characterized yeast strains carrying exogenous bacterial chromosomes that diverged from eukaryotic sequences over 1.5 billion years ago. By combining this synthetic approach with deep learning-based in silico analysis, we show that sequence composition drives chromatin assembly, transcriptional activity, folding, and compartmentalization in this cellular context. These results are also a step forward in understanding the molecular events at play following natural horizontal gene transfers, and could also be considered in synthetic genomic engineering projects.