Replication timing maintains the global epigenetic state in human cells

Abstract

The temporal order of DNA replication [replication timing (RT)] is correlated with chromatin modifications and three-dimensional genome architecture; however, causal links have not been established, largely because of an inability to manipulate the global RT program. We show that loss of RIF1 causes near-complete elimination of the RT program by increasing heterogeneity between individual cells. RT changes are coupled with widespread alterations in chromatin modifications and genome compartmentalization. Conditional depletion of RIF1 causes replication-dependent disruption of histone modifications and alterations in genome architecture. These effects were magnified with successive cycles of altered RT. These results support models in which the timing of chromatin replication and thus assembly plays a key role in maintaining the global epigenetic state.

BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

“…In fact, in post-mitotic cells, cohesin has been proven to be continuously required to sustain proper neuronal gene expression (Weiss et al, 2021). However, in the case of cycling cells, since cohesin associates with replication origins (Pherson et al, 2019) and temporal order of DNA replication correlates with chromatin modifications and three-dimensional genome architecture (Klein et al, 2021), it must be better investigated whether the effect on transcription could be related to replication perturbations, at least partially or in certain cellular contexts.…”

Collective regulation of chromatin modifications predicts replication timing during cell cycle

“…CTRs are large regions that contain many initiation sites that fire at the same time, coordinating the regional replication that can occur early or late ( Zhao et al, 2020 ). The CTRs that replicate in late S (LS) phase associate with heterochromatin enriched in H3K9me3 ( Klein et al, 2021 ; Zhao et al, 2020 ); however, other CTRs have different RT and chromatin states. For example, loss of a key replication factor Rif-1 disrupts ~40% of RT, but not all H3K9me3-containing CTRs ( Klein et al, 2021 ).…”

Asynchronous Replication Timing: A Mechanism for Monoallelic Choice During Development

“…Replication timing is also correlated with many important epigenetic features within the genome architecture (Rhind and Gilbert, 2013;Reverón-Gómez et al, 2018;Escobar et al, 2019). In keeping with this, several studies have provided more direct evidence that replication timing itself plays a key role in orchestrating and maintaining epigenetic states (Zhang et al, 2002;Klein et al, 2021).…”

“…This structural difference is set up early in the embryo and then maintained in all cell types where it can provide a template for preferentially activating one allele as opposed to the other. Thus, the choice of allele is a built-in part of replication-time-directed genome structure (Klein et al, 2021), waiting to be utilized in a specific manner in individual cell types. There is thus no need for "choosing" in trans over and over again in each cell, since the decision process itself has already been precoded in cis in all somatic cells.…”