High-Resolution Profiling of Drosophila Replication Start Sites Reveals a DNA Shape and Chromatin Signature of Metazoan Origins

Abstract

Summary At every cell cycle, faithful inheritance of metazoan genomes requires the concerted activation of thousands of DNA replication origins. However, the genetic and chromatin features defining metazoan replication start sites remain largely unknown. Here, we delineate the origin repertoire of the Drosophila genome at high resolution. We address the role of origin-proximal G-quadruplexes and suggest that they transiently stall replication forks in vivo. We dissect the chromatin configuration of replication origins and identify a rich spatial organization of chromatin features at initiation sites. DNA shape and chromatin configurations, not strict sequence motifs, mark and predict origins in higher eukaryotes. We further examine the link between transcription and origin firing and reveal that modulation of origin activity across cell types is intimately linked to cell-type-specific transcriptional programs. Our study unravels conserved origin features and provides unique insights into the relationship between DNA topology, chromatin, transcription and replication initiation across metazoa.

Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures

“…Next, we focused on the models learnt on TF binding profiles and sought to identify the chromatin features that contribute the most to model predictions by estimating feature stability coefficients using bootstrap-lasso (Comoglio and Paro 2014;Comoglio et al 2015). Intuitively, the more a feature is necessary for accurate predictions, the higher its stability value.…”

Regulation of DNA Replication through Natural Impediments in the Eukaryotic Genome

“…Interestingly, G-quadruplexes are extensively found near transcriptional start sites (TSS). Such DNA secondary structures at TSS may affect DNA topology, creating a dynamic equilibrium between duplex DNA and secondary conformation, in order to not only regulate transcription [182,183], but also control replication initiation [184,185,186]. Further studies are necessary to understand the mechanisms by which G-quadruplex DNA regulates multiple cellular processes.…”

Replicating Large Genomes: Divide and Conquer

“…RT changes during differentiation occur across half of the genome and analysis of multiple cell types allowed the identification of distinct types of domains: constitutive early replicating domains (CE), constitutive late replicating domains (CE) and developmentally regulated domains (Figure 4A). A surprise from these studies is that genome-wide correlations of chromatin properties to RT are driven by the constitutive half of the genome, including transcriptional activity (Rivera-Mulia et al, 2015), ORC binding sites (Lubelsky et al, 2014), origin efficiency (Besnard et al, 2012; Comoglio et al, 2015), gene density and GC content (Hiratani et al, 2010; Rivera-Mulia et al, 2015), DHSs (Pope et al, 2014), MNase sensitivity (Takebayashi et al, 2012) and Rif1 (Dileep et al, 2015a). By contrast, these same properties do not correlate with RT of developmentally regulated domains (Rivera-Mulia and Gilbert, 2016).…”