Emergence of replication timing during early mammalian development

Area of Science:

• Genomics
• Developmental Biology
• Epigenetics

Background:

• DNA replication timing (RT) is crucial for genetic inheritance and genome organization.
• RT is cell-type specific, linked to 3D nuclear organization, and acts as an epigenetic fingerprint.
• Developmental regulation of RT in mammals in vivo remains largely unexplored.

Purpose of the Study:

• To investigate the developmental regulation of replication timing in early mammalian embryos.
• To map genome-wide RT from zygote to blastocyst stages using single-cell Repli-seq.
• To understand the interplay between nuclear organization, transcription, and RT acquisition.

Main Methods:

• Single-cell Repli-seq for genome-wide RT mapping.
• Analysis of mouse embryos from zygote to blastocyst.
• Investigating the role of RNA polymerase II in RT definition.

Main Results:

• Replication timing is initially poorly defined in zygotes and becomes progressively defined from the 4-cell stage.
• The strengthening of A and B compartments coincides with RT definition.
• Transcription, particularly involving RNA polymerase II, contributes to RT precision during zygotic genome activation.
• Establishment of nuclear organization precedes defined RT features, priming genome partitioning.

Conclusions:

• Nuclear organization precedes and primes the acquisition of defined replication timing during early mammalian development.
• Transcription plays a key role in refining the replication timing program.
• This study provides insights into epigenome establishment and genome organization principles at the start of mammalian development.