Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types

Abstract

To identify evolutionarily conserved features of replication timing and their relationship to epigenetic properties, we profiled replication timing genome-wide in four human embryonic stem cell (hESC) lines, hESC-derived neural precursor cells (NPCs), lymphoblastoid cells, and two human induced pluripotent stem cell lines (hiPSCs), and compared them with related mouse cell types. Results confirm the conservation of coordinately replicated megabase-sized ''replication domains'' punctuated by origin-suppressed regions. Differentiation-induced replication timing changes in both species occur in 400-to 800-kb units and are similarly coordinated with transcription changes. A surprising degree of cell-type-specific conservation in replication timing was observed across regions of conserved synteny, despite considerable species variation in the alignment of replication timing to isochore GC/LINE-1 content. Notably, hESC replication timing profiles were significantly more aligned to mouse epiblast-derived stem cells (mEpiSCs) than to mouse ESCs. Comparison with epigenetic marks revealed a signature of chromatin modifications at the boundaries of early replicating domains and a remarkably strong link between replication timing and spatial proximity of chromatin as measured by Hi-C analysis. Thus, early and late initiation of replication occurs in spatially separate nuclear compartments, but rarely within the intervening chromatin. Moreover, cell-type-specific conservation of the replication program implies conserved developmental changes in spatial organization of chromatin. Together, our results reveal evolutionarily conserved aspects of developmentally regulated replication programs in mammals, demonstrate the power of replication profiling to distinguish closely related cell types, and strongly support the hypothesis that replication timing domains are spatially compartmentalized structural and functional units of three-dimensional chromosomal architecture.

DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes

“…Because cancers usually occur beyond the reproductive age, cancer traits would not be under direct selection pressure. However, many cancer-related genes are often involved in fundamental cellular processes such as development, cell cycle, and DNA repair, and these genes tend to be in early replicating regions 34 . A recent study has shown that replication timing is an evolvable property 35 .…”

Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape

“…The Hi-C study proposed that the genome is divided into two distinct compartments, an open compartment characterized by euchromatic features, such as histone 3 lysine 4 (H3K4) trimethlyation, and a closed compartment characterized by heterochromatic features, such as H3K9 methylation [120]. Importantly, DNA replication correlates to 3-D genome organization even more so than to transcription, with early replicating regions being mostly in the euchromatic compartment and late replicating ones in the heterochromatic one [116,121]. Thus, lack of global reorganization of DNA replication in preiPS cells might reflect a not properly reorganized global 3-D nuclear architecture, suggesting that nuclear architecture might be another barrier for reprogramming that is closely associated with replication timing control.…”

Spatio-Temporal Organization of Replication in Bacteria and Eukaryotes (Nucleoids and Nuclei)

“…As noted above, studies of nascent sites within nuclei show that a specific subset of potential initiation targets are select with good efficiency at the onset of the S phase (Jackson and Pombo 1998;Ma et al 1998). Numerous genome-wide studies have shown that active genes are preferentially replicated at the beginning of the S phase and the process of selection correlates with patterns of gene expression (Cadoret et al 2008;Farkash-Amar et al 2008), active chromatin marks (Hiratani et al 2008), and the mostly highly interactive gene regions defined by Hi-C (Ryba et al 2010). These observations imply that the local chromatin context is a key determinant of initiation at the onset of the S phase, with arguably the most mobile chromatin having the highest probability of engaging synthesis.…”

“…The underlying mechanisms that define these structures are likely to be very complex, so that the structure of chromatin domains correlates with numerous features of chromatin function. This is especially evident during cell differentiation, when subtle changes in higher-order chromatin architecture during differentiation provide an excellent correlation with changes in replication timing (Ryba et al 2010). …”