Replication Domains: Genome Compartmentalization into Functional Replication Units

Abstract

DNA replication occurs in a defined temporal order during S phase, known as the replication timing programme, which is regulated not only during the cell cycle but also during the process of development and differentiation. The units of replication timing regulation, known as replication domains (RDs), frequently comprise several nearly synchronously firing replication origins. Replication domains correspond to topologically associating domains (TADs) mapped by chromatin conformation capture methods and are likely to be the molecular equivalents of replication foci observed using cytogenetic methods. Both TAD and replication foci are considered to be stable structural units of chromosomes, conserved through the cell cycle and development, and accordingly, the boundaries of RDs also appear to be stable in different cell types. During both normal development and progression of disease, distinct cell states are characterized by unique replication timing signatures, with approximately half of genomic RDs switching replication timing between these cell states. Advances in functional genomics provide hope that we can soon gain an understanding of the cause and consequence of the replication timing programme and its myriad correlations with chromatin context and gene regulation.

Cohesin depleted cells rebuild functional nuclear compartments after endomitosis

“…We also examine replication domains (RDs). RDs defined by genome-wide Repli-Seq analyses are often considered to correspond to TADs mapped by Hi-C methods [27, 52] and as molecular equivalents of replication foci / domains observed by microscopic methods [53]. Yet, a direct comparison of these structures is a delicate issue since neither RDs nor TADs are strictly defined: microscopically observable replication sites were initially reported in rat fibroblast nuclei with an average DNA content of ∼1 Mb [54].…”

Common fragile site instability in normal cells: Lessons and perspectives

“…47 In summary, late and incomplete replication of large genes is not per se a sufficient condition for chromosome fragility at CFSs, whereas the tissue specificity of several CFSs 9 may be associated with the plasticity characterizing, in mammalian cells, both DNA replication 48,[52][53][54] and establishment of replication timing. [55][56][57] Furthermore, nucleosome position as well as DNA-binding proteins acting as regulators of the epigenetic landscape at CFSs 58 and histone-specific modifications may account for the replication patterns observed at CFSs. 59,60 An interesting finding in this context is the presence and the potential role at CFSs of the macroH2A1.2 histone variant that has been recently identified as an epigenetic mediator of replication stress response.…”

“…In addition, two regions lacking initiation events have been identified within FRA6E . In summary, late and incomplete replication of large genes is not per se a sufficient condition for chromosome fragility at CFSs, whereas the tissue specificity of several CFSs may be associated with the plasticity characterizing, in mammalian cells, both DNA replication and establishment of replication timing . Furthermore, nucleosome position as well as DNA‐binding proteins acting as regulators of the epigenetic landscape at CFSs and histone‐specific modifications may account for the replication patterns observed at CFSs .…”

Replication Timing Networks: a novel class of gene regulatory networks

“…Changes in gene activity and chromatin 3D organization are coordinated with dynamic changes in the temporal order of genome duplication, known as the replication timing (RT) program 25 Rivera-Mulia et al 2015;Hiratani et al 2008;Rivera-Mulia et al 2018a). Spatio-temporal control of RT is conserved in all eukaryotes (Solovei et al 2016;Rivera-Mulia and Gilbert 2016a;Zhao et al 2017) and alterations in the RT program are associated with different diseases (Ryba et al 2012;Gerhardt et al 2014;Rivera-Mulia et al 2017;Sasaki et al 2017). RT is regulated during development in discrete chromosome units, referred to as replication domains (RDs), that align with 30 topological associated domains (TADs) mapped by chromosome conformation capture techniques (Hi-C) and segregate into distinct nuclear compartments visualized by either cytogenetic or Hi-C methods (Jackson and Pombo 1998; Moindrot et al 2012;Pope et al 2014;Rivera-Mulia and Gilbert 2016b;Rivera-Mulia et al 2018a;Ryba et al 2010;Sadoni et al 2004;Yaffe et al 2010).…”