Systematic determination of replication activity type highlights interconnections between replication, chromatin...

Area of Science:

• Genomics
• Molecular Biology
• Computational Biology

Background:

• DNA replication timing (ToR) is a crucial, regulated genomic process.
• Genome-wide studies reveal ToR associations with genomic features and conservation across mammals.
• The genome is organized into constant ToR regions (CTRs) and temporal transition regions (TTRs) based on replication speed.

Purpose of the Study:

• To develop a computational tool, ARTO, for precise genome-wide ToR determination and replication activity type classification (CTR vs. TTR).
• To analyze replication timing plasticity and its relationship with chromatin structure and nuclear organization.

Main Methods:

• Developed ARTO, a computational tool utilizing signal processing to fit piece-wise linear curves to raw replication timing data.
• Applied ARTO to mouse and human ToR data for genome-wide analysis.
• Integrated ToR data with chromosome organization characteristics.

Main Results:

• ARTO enables precise genome-wide ToR determination and CTR/TTR characterization.
• Significant ToR differences (10-25%) were observed across different tissue types, highlighting replication program plasticity.
• Late ToR is associated with repressive chromatin marks in both CTRs and TTRs.
• TTRs exhibit compact chromatin and are located closer to the nuclear envelope compared to CTRs.

Conclusions:

• ARTO is a valuable tool for analyzing DNA replication timing and organization.
• Replication timing is dynamic and tissue-specific, influenced by chromatin structure and nuclear positioning.
• Replication timing plays a role in shaping regional chromatin structure.