ProA and ProB repeat sequences shape genome organization in eukaryotes

Abstract

Genome organization is partially conserved across cell types, yet its DNA-encoded determinants remain incompletely understood. Here we define ProA and ProB repeat sequences (RepSeqs) as two classes of cis-elements that promote A/euchromatin or B/heterochromatin compartment identity. We show that relative ProA/ProB density predicts Hi-C compartment profiles, indicating that compartmental propensity is largely encoded in sequence composition, and point to specific chromatin-based mechanisms underlying these effects. ProA RepSeqs are predominantly Alu elements, whereas ProB RepSeqs comprise young LINE-1s, selected ERVs, AT-rich microsatellites, and satellite repeats. RepSeqs of more indefinite character, including transcriptional enhancers, can switch between ProA and ProB functions to open or close chromatin domains in a context-dependent manner. In cancer, CpG methylation loss disproportionately impacts ProB RepSeqs, weakening the B compartment and thereby contributing to genome unfolding and cancer cell plasticity.