Huvet, M. et al. Human gene organization driven by the coordination of replication and transcription. Genome Res. 17, 1278-1285

Centre de Génétique Moléculaire (CNRS), 91198 Gif-sur-Yvette, France.
Genome Research (Impact Factor: 14.63). 10/2007; 17(9):1278-85. DOI: 10.1101/gr.6533407
Source: PubMed


In this work, we investigated a large-scale organization of the human genes with respect to putative replication origins. We developed an appropriate multiscale method to analyze the nucleotide compositional skew along the genome and found that in more than one-quarter of the genome, the skew profile presents characteristic patterns consisting of successions of N-shaped structures, designated here N-domains, bordered by putative replication origins. Our analysis of recent experimental timing data confirmed that, in a number of cases, domain borders coincide with replication initiation zones active in the early S phase, whereas the central regions replicate in the late S phase. Around the putative origins, genes are abundant and broadly expressed, and their transcription is co-oriented with replication fork progression. These features weaken progressively with the distance from putative replication origins. At the center of domains, genes are rare and expressed in few tissues. We propose that this specific organization could result from the constraints of accommodating the replication and transcription initiation processes at chromatin level, and reducing head-on collisions between the two machineries. Our findings provide a new model of gene organization in the human genome, which integrates transcription, replication, and chromatin structure as coordinated determinants of genome architecture.

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Available from: Maxime Huvet, Mar 14, 2014
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    • "Hence, RT constitutes a very informative functional readout of large-scale chromatin organization across distinct cell types and its regulation during development. Early replication is globally associated with active gene expression in all multicellular organisms (Schübeler et al. 2002, 2004; MacAlpine 2004 Q3 ; Woodfine et al. 2004; Huvet et al. 2007; Desprat et al. 2009; Hiratani et al. 2009; Schwaiger et al. 2009; Maric and Prioleau 2010; Lubelsky et al. 2014), and developmentally regulated changes in RT are generally coordinated with transcriptional competence (Zhou et al. 2002; Hiratani et al. 2008, 2010; Desprat et al. 2009; Schultz et al. 2010; Yue et al. 2014). However, causal relationships between RT and gene expression remain a longstanding puzzle. "
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    ABSTRACT: Duplication of the genome in mammalian cells occurs in a defined temporal order referred as its replication-timing (RT) program. RT changes dynamically during development, regulated in units of 400-800 kb referred as replication domains (RDs). Changes in RT are generally coordinated with transcriptional competence and changes in sub-nuclear position. We generated genome-wide RT profiles for 26 distinct human cell types including embryonic stem cell (hESC)-derived, primary cells and established cell lines representing intermediate stages of endoderm, mesoderm, ectoderm and neural crest (NC) development. We identified clusters of RDs that replicate at unique times in each stage (RT signatures) and confirmed global consolidation of the genome into larger synchronously replicating segments during differentiation. Surprisingly, transcriptome data revealed that the well-accepted correlation between early replication and transcriptional activity was restricted to RT-constitutive genes, whereas two thirds of the genes that switched RT during differentiation were strongly expressed when late replicating in one or more cell types. Closer inspection revealed that transcription of this class of genes was frequently restricted to the lineage in which the RT switch occurred, but was induced prior to a late to early RT switch and/or down-regulated after an early to late RT switch. Analysis of transcriptional regulatory networks showed that this class of genes contains strong regulators of genes that were only expressed when early replicating. These results provide intriguing new insight into the complex relationship between transcription and RT regulation during human development. Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · Jun 2015 · Genome Research
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    • "enome stability . The organization of bacterial genomes imparts in fact a co - orientation bias of replication and transcription of highly expressed and / or essen - tial genes , thus avoiding deleterious head - on conflicts ( Rocha , 2008 ) . A preference for co - orientation of replication and tran - scription was also observed in human genome ( Huvet et al . , 2007 ) . Moreover , head - on replication – transcription collisions are prevented by specific fork barriers at highly expressed riboso - mal DNA ( rDNA ) in eukaryotic organisms ( Kobayashi , 2014 ) . From bacteria to humans , actively transcribed genes exhibit ele - vated spontaneous mutation and recombination rates , which are stimulated "
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    ABSTRACT: DNA replication and transcription are vital cellular processes during which the genetic information is copied into complementary DNA and RNA molecules. Highly complex machineries required for DNA and RNA synthesis compete for the same DNA template, therefore being on a collision course. Unscheduled replication-transcription clashes alter the gene transcription program and generate replication stress, reducing fork speed. Molecular pathways and mechanisms that minimize the conflict between replication and transcription have been extensively characterized in prokaryotic cells and recently identified also in eukaryotes. A pathological outcome of replication-transcription collisions is the formation of stable RNA:DNA hybrids in molecular structures called R-loops. Growing evidence suggests that R-loop accumulation promotes both genetic and epigenetic instability, thus severely affecting genome functionality. In the present review, we summarize the current knowledge related to replication and transcription conflicts in eukaryotes, their consequences on genome instability and the pathways involved in their resolution. These findings are relevant to clarify the molecular basis of cancer and neurodegenerative diseases.
    Full-text · Article · Apr 2015 · Frontiers in Genetics
    • "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]. "
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    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
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