Emergence of replication timing during early mammalian development

Abstract

DNA replication enables genetic inheritance across the kingdoms of life. Replication occurs with a defined temporal order known as the replication timing (RT) programme, leading to organization of the genome into early- or late-replicating regions. RT is cell-type specific, is tightly linked to the three-dimensional nuclear organization of the genome1,2 and is considered an epigenetic fingerprint3. In spite of its importance in maintaining the epigenome4, the developmental regulation of RT in mammals in vivo has not been explored. Here, using single-cell Repli-seq5, we generated genome-wide RT maps of mouse embryos from the zygote to the blastocyst stage. Our data show that RT is initially not well defined but becomes defined progressively from the 4-cell stage, coinciding with strengthening of the A and B compartments. We show that transcription contributes to the precision of the RT programme and that the difference in RT between the A and B compartments depends on RNA polymerase II at zygotic genome activation. Our data indicate that the establishment of nuclear organization precedes the acquisition of defined RT features and primes the partitioning of the genome into early- and late-replicating domains. Our work sheds light on the establishment of the epigenome at the beginning of mammalian development and reveals the organizing principles of genome organization.

Reconstitution of chromatin reorganization during mammalian oocyte development

“…Degrading RNAPII using triptolide, α-amanitin or auxin-inducible degron results in little changes in the gross morphology of chromatin in other systems 56,[65][66][67][68][69][70] , including early mammalian embryos [71][72][73][74][75][76] . Why does RNAPII degradation have more profound impacts on chromatin in mammalian oocytes than in other systems?…”

DNA Damage, Genome Stability, and Adaptation: A Question of Chance or Necessity?

“…This spatial compartmentalization also imposes temporal compartmentalization according to a replication timing (RT) program [70]: EC replicates early during the S-phase of the cell cycle and HC replicates late. Late-replicating DNA protects the genome and cell against mitotic catastrophe, or premature entry into the mitotic phase, which would damage unreplicated gene-dense EC and cause apoptosis.…”