Master transcription-factor binding sites constitute the core of early replication control elements.

Area of Science:

• Genomics
• Epigenetics
• Molecular Biology

Background:

• Eukaryotic genomes replicate according to a specific temporal order known as the replication timing (RT) program.
• Replication timing is developmentally regulated and influences cell fate transitions, but the underlying mechanisms are not fully understood.

Purpose of the Study:

• To elucidate the mechanisms controlling replication timing (RT).
• To investigate the role of Early Replication Control Elements (ERCEs) in regulating RT, transcription, and chromatin architecture.

Main Methods:

• Deletion analysis of cis-acting elements (ERCEs and subERCEs) in mouse embryonic stem cells (mESCs).
• Assessment of effects on transcription and replication timing.
• Analysis of transcription start sites.

Main Results:

• Early Replication Control Elements (ERCEs) are compound elements, with their RT activity largely attributable to multiple transcription factor binding sites (subERCEs).
• Deletion of subERCEs significantly impacted both transcription and replication timing.
• Deletion of transcription start sites abolished transcription but only moderately affected replication timing.

Conclusions:

• SubERCEs function as transcriptional enhancers that also structurally organize chromatin domains to promote early replication timing.
• This mechanism may create a feed-forward loop, driving significant epigenomic changes during cell fate transitions.