Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish...

Area of Science:

• Genomics
• Developmental Biology
• Epigenetics

Background:

• Replication timing, the process of duplicating DNA, is crucial for cell division and genome stability.
• Understanding conserved features of replication timing across species and its relation to epigenetic modifications is key to deciphering genome regulation.
• Previous studies have identified large-scale replication domains but lacked detailed cross-species comparisons and integration with 3D genome architecture.

Purpose of the Study:

• To identify evolutionarily conserved features of DNA replication timing.
• To investigate the relationship between replication timing and epigenetic properties across different mammalian cell types.
• To explore the role of 3D chromatin organization in replication timing.

Main Methods:

• Genome-wide replication timing profiling in human embryonic stem cells (hESCs), neural precursor cells (NPCs), lymphoblastoid cells, induced pluripotent stem cells (hiPSCs), and their mouse counterparts.
• Comparison of replication timing profiles across species and cell types, including analysis of conserved synteny.
• Integration of replication timing data with epigenetic marks and 3D genome structure data (Hi-C).

Main Results:

• Confirmed conservation of large replication domains and origin-suppressed regions.
• Identified conserved, coordinated changes in replication and transcription during differentiation in both species.
• Observed significant cell-type-specific conservation of replication timing, with human ESCs aligning more closely with mouse epiblast-derived stem cells (mEpiSCs) than mouse ESCs.
• Found a strong correlation between replication timing, chromatin modifications at domain boundaries, and spatial proximity of chromatin as measured by Hi-C.
• Demonstrated that early and late replication initiation occurs in spatially segregated nuclear compartments.

Conclusions:

• Replication timing programs are evolutionarily conserved in mammals and linked to 3D genome organization.
• Replication timing profiling effectively distinguishes closely related cell types.
• Replication timing domains represent spatially compartmentalized structural and functional units of the 3D genome.
• Cell-type-specific conservation implies conserved developmental changes in chromatin spatial organization.