Article

Replication Fork Polarity Gradients Revealed by Megabase-Sized U-Shaped Replication Timing Domains in Human Cell Lines

Université de Lyon, Lyon, France.
PLoS Computational Biology (Impact Factor: 4.62). 04/2012; 8(4):e1002443. DOI: 10.1371/journal.pcbi.1002443
Source: PubMed

ABSTRACT

In higher eukaryotes, replication program specification in different cell types remains to be fully understood. We show for seven human cell lines that about half of the genome is divided in domains that display a characteristic U-shaped replication timing profile with early initiation zones at borders and late replication at centers. Significant overlap is observed between U-domains of different cell lines and also with germline replication domains exhibiting a N-shaped nucleotide compositional skew. From the demonstration that the average fork polarity is directly reflected by both the compositional skew and the derivative of the replication timing profile, we argue that the fact that this derivative displays a N-shape in U-domains sustains the existence of large-scale gradients of replication fork polarity in somatic and germline cells. Analysis of chromatin interaction (Hi-C) and chromatin marker data reveals that U-domains correspond to high-order chromatin structural units. We discuss possible models for replication origin activation within U/N-domains. The compartmentalization of the genome into replication U/N-domains provides new insights on the organization of the replication program in the human genome.

Download full-text

Full-text

Available from: Arach Goldar
  • Source
    • "To ensure that this estimation is robust, we recalculated FP from RT at distances ranging between 0.5 and 15 kb from the current coordinate; all resulting values were strongly correlated (Spearman's ρ > 0.995). Absolute values of RT change reflect the propensity of FP toward unidirectionality (Baker et al. 2012). We divided the genome into nine bins according to the values of FP: eight bins each containing 10% of all nucleotides, and one bin centered at FP = 0, containing 20% of all nucleotides. "
    [Show abstract] [Hide abstract]
    ABSTRACT: APOBEC3A and APOBEC3B, cytidine deaminases of the APOBEC family, are among the main factors causing mutations in human cancers. APOBEC deaminates cytosines in single-stranded DNA (ssDNA). A fraction of the APOBEC-induced mutations occur as clusters ("kataegis") in single-stranded DNA produced during repair of double-stranded breaks (DSBs). However, the properties of the remaining 87% of nonclustered APOBEC-induced mutations, the source and the genomic distribution of the ssDNA where they occur, are largely unknown. By analyzing genomic and exomic cancer databases, we show that >33% of dispersed APOBEC-induced mutations occur on the lagging strand during DNA replication, thus unraveling the major source of ssDNA targeted by APOBEC in cancer. Although methylated cytosine is generally more mutation-prone than nonmethylated cytosine, we report that methylation reduces the rate of APOBEC-induced mutations by a factor of roughly two. Finally, we show that in cancers with extensive APOBEC-induced mutagenesis, there is almost no increase in mutation rates in late replicating regions (contrary to other cancers). Because late-replicating regions are depleted in exons, this results in a 1.3-fold higher fraction of mutations residing within exons in such cancers. This study provides novel insight into the APOBEC-induced mutagenesis and describes the peculiarity of the mutational processes in cancers with the signature of APOBEC-induced mutations.
    Full-text · Article · Jan 2016 · Genome Research
    • "Recent application of graph theory [57] [86] has confirmed the central position of the MaOris in the chromatin interaction network: they form a set of interconnected hubs of chromatin interactions both within and between different human chromosomes. The additional observation of a remarkable gene organization in U/N-domains with a significant enrichment of expressed genes nearby the bordering MaOris [72] [77] [84] [87] prompted the interpretation of these replication domains as chromatin units of highly coordinated regulation of transcription and replication [14] [53] [57]. The analysis of the spatial proximity of evolutionary breakpoints between human and mouse further showed that some aspects of genome 3D architecture are conserved across very large evolutionary distances [62] [64] [88] [89]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent analysis of genome-wide epigenetic modification data, mean replication timing (MRT) profiles and chromosome conformation data in mammals have provided increasing evidence that flexibility in replication origin usage is regulated locally by the epigenetic landscape and over larger genomic distances by the 3D chromatin architecture. Here, we review the recent results establishing some link between replication domains and chromatin structural domains in pluripotent and various differentiated cell types in human. We reconcile the originally proposed dichotomic picture of early and late constant timing regions that replicate by multiple rather synchronous origins in separated nuclear compartments of open and closed chromatins, with the U-shaped MRT domains bordered by "master" replication origins specified by a localized (∼200-300kb) zone of open and transcriptionally active chromatin from which a replication wave likely initiates and propagates toward the domain center via a cascade of origin firing. We discuss the relationships between these MRT domains, topologically associated domains and lamina-associated domains. This review sheds a new light on the epigenetically regulated global chromatin reorganization that underlies the loss of pluripotency and the determination of differentiation properties. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
    No preview · Article · Apr 2015 · FEBS letters
  • Source
    • "Hundreds of megabase-sized domains with a U-shaped timing profile were identified independent of skew analysis (Baker et al., 2012; Audit et al., 2013). Demonstrating that the timing gradient equaled the ratio of fork speed to fork directionality led us to predict an N-shaped fork directionality profile of U domains strikingly similar to skew N domains (Guilbaud et al., 2011; Baker et al., 2012). U domains coincided with chromatin modification seems too abundant (80% of all H4 molecules) to explain origin specificity (Schotta et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Replication of mammalian genomes starts at sites termed replication origins, which historically have been difficult to locate as a result of large genome sizes, limited power of genetic identification schemes, and rareness and fragility of initiation intermediates. However, origins are now mapped by the thousands using microarrays and sequencing techniques. Independent studies show modest concordance, suggesting that mammalian origins can form at any DNA sequence but are suppressed by read-through transcription or that they can overlap the 5' end or even the entire gene. These results require a critical reevaluation of whether origins form at specific DNA elements and/or epigenetic signals or require no such determinants. © 2015 Hyrien.
    Preview · Article · Jan 2015 · The Journal of Cell Biology
Show more