Genome architecture in budding yeast

The genome of metazoan cells is organized into topologicallyassociating domains (TADs) that have similar histone modifications,transcription level, and DNA replication timing. Although similarstructures appear to be conserved in fission yeast, computationalmodeling and analysis of high-throughput chromosome conformationcapture (Hi-C) data have been used to argue that the small,highly constrained budding yeast chromosomes could not havethese structures. In contrast, hereinwe analyze Hi-C data for buddingyeast and identify 200-kb scale TADs, whose boundaries are enrichedfor transcriptional activity. Furthermore, these boundaries separateregions of similarly timed replication origins connecting the longQ:11 known effect of genomic context on replication timing to genomearchitecture. To investigate the molecular basis of TAD formation,we performed Hi-C experiments on cells depleted for the Forkheadtranscription factors, Fkh1 and Fkh2, previously associated with replicationtiming. Forkhead factors do not regulate TAD formation, butdo promote longer-range genomic interactions and control interactionsbetween origins near the centromere. Thus, our work definesspatial organization within the budding yeast nucleus, demonstratesthe conserved role of genome architecture in regulating DNA replication,and identifies a molecular mechanism specifically regulatinginteractions between pericentric origins.