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

Abstract

AbstractGenomic 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 directly explore the causal 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. Combining this synthetic approach with a deep learning-based analysis, we show that, in this cellular context, the sequence composition drives nucleosome assembly, transcriptional activity, cohesin-mediated looping, and chromatin compartmentalization. These results are a step forward in understanding the molecular events at play during natural horizontal gene transfers as well as synthetic genomics engineering projects.