Replication timing maintains the global epigenetic state in human cells.

Area of Science:

• Genetics
• Epigenetics
• Molecular Biology

Background:

• Replication timing (RT) correlates with chromatin modifications and 3D genome architecture.
• Causal links between RT and these features remain unestablished due to limitations in manipulating the global RT program.

Purpose of the Study:

• To investigate the causal role of the replication timing program in maintaining epigenetic states.
• To explore the consequences of manipulating the global RT program.

Main Methods:

• Utilized conditional depletion of RIF1 to eliminate the global replication timing program.
• Analyzed changes in chromatin modifications, genome compartmentalization, and histone modifications.
• Observed effects across successive cycles of altered RT.

Main Results:

• Loss of RIF1 led to near-complete elimination of the RT program, increasing cell-to-cell heterogeneity.
• RT alterations were coupled with widespread changes in chromatin modifications and genome compartmentalization.
• Conditional RIF1 depletion caused replication-dependent disruption of histone modifications and genome architecture, effects magnified over successive cycles.

Conclusions:

• Replication timing plays a key role in maintaining the global epigenetic state.
• The timing of chromatin replication and assembly is critical for epigenetic regulation.