Replication timing networks reveal a link between transcription regulatory circuits and replication timing control

Area of Science:

• Genomics
• Molecular Biology
• Developmental Biology

Background:

• DNA replication timing (RT) is a crucial process regulated during development, linked to genome organization and transcription.
• The precise coordination between transcription and RT is not fully understood, suggesting indirect regulatory mechanisms.

Purpose of the Study:

• To construct and analyze replication timing (RT) regulatory networks across diverse human cell types and differentiation stages.
• To investigate the relationship between RT, genome organization, and transcriptional regulatory networks (TRNs).

Main Methods:

• Genome-wide RT profiling across 15 human cell types and human embryonic stem cell differentiation stages.
• Construction of coordinated and directional RT regulatory networks.
• Integration of RT networks with transcriptional regulatory networks (TRNs) to form composite and bipartite networks.

Main Results:

• Developed complex RT regulatory networks with thousands of interactions, revealing functional subnetwork communities.
• Identified master regulators coordinating RT changes within cell lineages during differentiation.
• Discovered novel *trans* interactions linking core cell-type-specific transcription factors to RT changes, with evidence of cooperative binding.

Conclusions:

• Cell-type-specific transcription factors play a significant role in directing replication timing.
• A regulatory link exists between the establishment of transcriptional regulatory networks and replication timing control during lineage specification.