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Post-replicative chromatin accessibility predicts cell fate change.

ABSTRACT: It has long been hypothesized that DNA replication is important in reconfiguring the chromatin landscape during cell identity changes in development, disease, and reprogramming contexts. There is now a large body of work showing that DNA replication indeed alters chromatin structure and composition, but a function for these changes has remained elusive. Using replication-coupled ATAC-seq in differentiating embryonic stem cells and reprogramming mouse embryonic fibroblasts, we profiled replicated and unreplicated chromatin within the same cells and observed de novo chromatin opening specifically in the replicated fraction. These opening events created an accessibility landscape similar to that seen in the unreplicated fraction from later timepoints, especially in reprogramming. By parsing reprogramming fibroblasts based on proliferative history, we confirmed that reprogramming potential can be predicted by proliferation rate. This work bridges the gap between replication-induced structural chromatin changes and functional consequences by demonstrating that replication facilitates a “window of opportunity” that advances the chromatin landscape during cell identity change.

ORGANISM(S): Mus musculus

PROVIDER: GSE296014 | GEO | 2026/02/19

REPOSITORIES: GEO

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Project description:Cohesin organizes the genome into spatially segregated loops and topologically associated domains by loop extrusion. In addition, it ensures cohesion of sister chromatids after replication. Thus, cohesin is expected to limit chromatin dynamics by ensuring cohesion and compacting chromatin in the interphase. Nonetheless, loop extrusion is an example of chromatin dynamics; thus, cohesin could promote the dynamics of genomic loci at the scale of individual loops and contact domains. Moreover, given that the extruding activity of cohesin after replication is supplemented by its cohesive activity, the impact of cohesin on chromatin dynamics in different phases of the cell cycle may vary. Of particular interest is the cohesin’s role in the regulation of the dynamics of damaged chromatin, which remains insufficiently studied. Here, we visualized a genomic locus using the CRISPR-Sirius system in human cells with auxin-induced depletion of the cohesin subunit RAD21. Cohesin depletion increased the local spatial dynamics of the visualized locus on a time scale of fractions of a second to one minute. This effect was observed in both replicated and unreplicated chromatin. However, the increase in the mobility of the visualized locus upon cohesin depletion was more pronounced in the former. In addition, we showed that cohesin depletion did not affect the local mobility of double-strand break repair foci visualized using a fluorescent fragment of the repair factor 53BP1. Cohesin depletion did not affect the local mobility of repair foci in either replicated or unreplicated chromatin. The results indicate that cohesin constrains local spatial dynamics of genomic loci. At the same time, cohesive activity of cohesin is not indispensable for restricting chromatin dynamics, although it enhances the confinement effect. On the other hand, repair foci are less mobile structures than point chromatin loci, and cohesin does not affect their dynamics on the studied time scales.

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Post-replicative chromatin accessibility predicts cell fate change.

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