The chromatin environment shapes DNA replication origin organization and defines origin classes

Area of Science:

• Cell Biology
• Genetics
• Epigenetics

Background:

• Metazoan replication origins are crucial for DNA duplication but remain poorly understood.
• High-resolution identification of these origins is needed to elucidate their regulatory mechanisms.

Purpose of the Study:

• To identify and characterize metazoan replication origins genome-wide in mouse ES cells.
• To differentiate initiation sites (IS) and initiation zones (IZ).
• To integrate origin data with chromatin marks and factors to understand regulatory landscapes.

Main Methods:

• Genome-wide identification of replication origins at high resolution in mouse ES cells.
• Characterization of genetic signatures, organization, and sequence motifs.
• Integration of origin data with 43 chromatin marks and factors.

Main Results:

• Replication origins were classified into three distinct classes (Class 1, 2, 3) based on organization, chromatin environment, and sequence motifs.
• Class 1 origins are isolated, low-efficiency, late-replicating, and enriched in AC repeats.
• Class 2 origins are enhancer-rich, while Class 3 origins are efficient, associated with open chromatin, and polycomb-enriched.
• Origin G-rich Repeated elements (OGREs) forming G-quadruplexes (G4) were found near initiation sites, associated with labile nucleosomes (H3K64ac).

Conclusions:

• Specific chromatin landscapes and genetic signatures regulate replication origin localization.
• Origin plasticity in multicellular eukaryotes is driven by synergistic combinations of genetic features and chromatin configurations.
• These findings explain links between DNA replication and transcription and highlight adaptive origin profiles.