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ProA and ProB repeat sequences shape genome organization, and enhancers open domains

Bonnet, K. A.; Hulo, N.; Mourad, R.; Ewing, A.; Croce, O.; Naville, M.; Vassetzky, N.; Gilson, E.; Picard, D.; Fourel, G.

2023-10-29 genetics
10.1101/2023.10.27.564043 bioRxiv
Show 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.

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