Sequencing newly replicated DNA reveals widespread plasticity in human replication timing

Area of Science:

• Genomics
• Epigenetics
• Cell Biology

Background:

• Faithful DNA replication ensures genetic material transmission to daughter cells.
• Replication timing is crucial for epigenetic state inheritance.
• Understanding replication patterns across cell types is key to cell-lineage specification.

Purpose of the Study:

• To develop a genome-scale method for mapping temporally ordered DNA replication.
• To investigate regional variations in human DNA replication time across diverse cell types.
• To explore the relationship between replication timing, chromatin accessibility, and gene expression.

Main Methods:

• Developed Repli Seq, a genome-scale approach using massively parallel sequencing.
• Applied Repli Seq to cytometry-fractionated cells (as few as 8,000).
• Analyzed high-resolution DNA replication patterns relative to cell-cycle time and genomic position.

Main Results:

• Identified cell-type-specific replication signatures with significant regional plasticity (≥50% of the genome).
• Discovered autosomal regions with biphasic replication timing, including known and novel domains of monoallelic expression.
• Found DNA replication initiates in accessible chromatin foci and correlates better with chromatin accessibility than gene expression.

Conclusions:

• Replication timing patterns exhibit extensive plasticity during cell-lineage specification.
• Replication timing is closely linked to chromatin accessibility, providing insights into genome compartmentalization.
• The findings offer a genome-wide view of epigenetic compartmentalization and its dynamic nature.