Genomic sequences co-evolve with DNA-associated proteins to ensure the multiscale folding of long DNA molecules into functional chromosomes. In eukaryotes, different molecular complexes organize the chromosome’s hierarchical structure, ranging from nucleosomes and cohesin- mediated DNA loops to large scale chromatin compartments. To explore the relationships between the DNA sequence composition and the spontaneous loading and activity of these DNA-associated complexes in the absence of co-evolution, we characterized chromatin assembly and activity in yeast strains carrying exogenous bacterial chromosomes that diverged from eukaryotic sequences over 1.5 billion years ago. We show that nucleosome assembly, transcriptional activity, cohesin-mediated looping, and chromatin compartmentalization can occur in a bacterial chromosome with a largely divergent sequence integrated in a eukaryotic host, and that the chromatinization of bacterial chromosomes is highly correlated with their sequence composition. These results are a step forward in understanding how foreign sequences are interpreted by a host nuclear machinery during natural horizontal gene transfers, as well as in synthetic genomics projects.Read less <