In eukaryotes, chromatin state and nuclear architecture are tightly linked to the replication timing (RT) program. Here, we consider how chromatin features operate across all scales of genome organization in mammals, from the local nucleosomal level, with histone variants and their posttranslational modifications, to the global scale that comprises compartments and topologically associated domains (TADs). We discuss recent findings that tie these features with DNA replication; we examine how histone variants and modifications shape replication initiation, how 3D genome architecture may contribute to temporal regulation, and how these local and global scales operate during early mammalian development, when RT emerges de novo. This overview will encourage dissection of principles that establish and maintain RT. • Histone variants, more than PTMs, strongly shape replication initiation sites. • Replication timing can be uncoupled from 3D genome architecture in somatic cells. • H3.3-H3.1 boundaries define early initiation zones independently of compartments. • RIF1 modulates replication timing without directly specifying nuclear organization. • Early development reveals de novo replication timing from local chromatin features.
Nunez-Vazquez et al. (Mon,) studied this question.