Global early replication disrupts gene expression and chromatin conformation in a single cell cycle

Abstract

Background The early embryonic divisions of many organisms, including fish, flies, and frogs, are characterized by a very rapid S-phase caused by high rates of replication initiation. In somatic cells, S-phase is much longer due to both a reduction in the total number of initiation events and the imposition of a temporal order of origin activation. The physiological importance of changes in the rate and timing of replication initiation in S-phase remains unclear. Results Here we assess the importance of the temporal control of replication initiation using a conditional system in budding yeast to drive the early replication of the majority of origins in a single cell cycle. We show that global early replication disrupts the expression of over a quarter of all genes. By deleting individual origins, we show that delaying replication is sufficient to restore normal gene expression, directly implicating origin firing control in this regulation. Global early replication disrupts nucleosome positioning and transcription factor binding during S-phase, suggesting that the rate of S-phase is important to regulate the chromatin landscape. Conclusions Together, these data provide new insight into the role of the temporal control of origin firing during S-phase for coordinating replication, gene expression, and chromatin establishment as occurs in the early embryo.

Spatiotemporal kinetics of CAF-1-dependent chromatin maturation ensures transcription fidelity during S-phase

“…Consistent with the transient delay we observed in nucleosome deposition and maturation in the absence of CAF-1, we found that the loss of silencing and cryptic transcription phenotypes were transient and confined to S-phase. Similarly, the deregulation of the DNA replication timing program leads to S-phase-specific transcriptional changes which mimic those caused by defects in chromatin assembly factors, presumably because the chromatin assembly machinery cannot keep pace with the rapid replication rate resulting in transient defects in histone assembly (Santos et al 2022). The S-phase-specific increase in gene expression from the subtelomeric regions of the chromosomes suggests that the re-establishment of silencing following passage of the fork was initially impaired but later recovered following chromatin maturation.…”