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Publications
Replication program and genome instability
Year of publication 2012
Benjamin Audit, Lamia Zaghloul, Antoine Baker, Alain Arneodo, Chun-Long Chen, Yves
d'Aubenton-Carafa, Claude Thermes (2012 Nov 15)
Megabase replication domains along the human genome: relation to chromatin
structure and genome organisation.
Sub-cellular biochemistry : 57-80 : DOI : 10.1007/978-94-007-4525-4_3
Summary
In higher eukaryotes, the absence of specific sequence motifs, marking the origins of
replication has been a serious hindrance to the understanding of (i) the mechanisms that
regulate the spatio-temporal replication program, and (ii) the links between origins
activation, chromatin structure and transcription. In this chapter, we review the partitioning
of the human genome into megabased-size replication domains delineated as N-shaped
motifs in the strand compositional asymmetry profiles. They collectively span 28.3% of the
genome and are bordered by more than 1,000 putative replication origins. We recapitulate
the comparison of this partition of the human genome with high-resolution experimental
data that confirms that replication domain borders are likely to be preferential replication
initiation zones in the germline. In addition, we highlight the specific distribution of
experimental and numerical chromatin marks along replication domains. Domain borders
correspond to particular open chromatin regions, possibly encoded in the DNA sequence, and
around which replication and transcription are highly coordinated. These regions also present
a high evolutionary breakpoint density, suggesting that susceptibility to breakage might be
linked to local open chromatin fiber state. Altogether, this chapter presents a
compartmentalization of the human genome into replication domains that are landmarks of
the human genome organization and are likely to play a key role in genome dynamics during
evolution and in pathological situations.
A Baker, H Julienne, C L Chen, B Audit, Y d'Aubenton-Carafa, C Thermes, A Arneodo (2012 Sep
25)
Linking the DNA strand asymmetry to the spatio-temporal replication program.
I. About the role of the replication fork polarity in genome evolution.
The European physical journal. E, Soft matter : 92
Summary
Two key cellular processes, namely transcription and replication, require the opening of the
DNA double helix and act differently on the two DNA strands, generating different mutational
patterns (mutational asymmetry) that may result, after long evolutionary time, in different
nucleotide compositions on the two DNA strands (compositional asymmetry). We elaborate
on the simplest model of neutral substitution rates that takes into account the strand
asymmetries generated by the transcription and replication processes. Using perturbation
theory, we then solve the time evolution of the DNA composition under strand-asymmetric
substitution rates. In our minimal model, the compositional and substitutional asymmetries
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Publications
Replication program and genome instability
are predicted to decompose into a transcription- and a replication-associated components.
The transcription-associated asymmetry increases in magnitude with transcription rate and
changes sign with gene orientation while the replication-associated asymmetry is
proportional to the replication fork polarity. These results are confirmed experimentally in
the human genome, using substitution rates obtained by aligning the human and
chimpanzee genomes using macaca and orangutan as outgroups, and replication fork
polarity determined in the HeLa cell line as estimated from the derivative of the mean
replication timing. When further investigating the dynamics of compositional skew evolution,
we show that it is not at equilibrium yet and that its evolution is an extremely slow process
with characteristic time scales of several hundred Myrs.
Antoine Baker, Benjamin Audit, Chun-Long Chen, Benoit Moindrot, Antoine Leleu, Guillaume
Guilbaud, Aurélien Rappailles, Cédric Vaillant, Arach Goldar, Fabien Mongelard, Yves d'AubentonCarafa, Olivier Hyrien, Claude Thermes, Alain Arneodo (2012 Apr 13)
Replication fork polarity gradients revealed by megabase-sized U-shaped
replication timing domains in human cell lines.
PLoS computational biology : e1002443 : DOI : 10.1371/journal.pcbi.1002443
Summary
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.
Guillaume Guilbaud, Aurélien Rappailles, Antoine Baker, Chun-Long Chen, Alain Arneodo, Arach
Goldar, Yves d'Aubenton-Carafa, Claude Thermes, Benjamin Audit, Olivier Hyrien (2012 Jan 6)
Evidence for sequential and increasing activation of replication origins along
replication timing gradients in the human genome.
PLoS computational biology : e1002322 : DOI : 10.1371/journal.pcbi.1002322
Summary
Genome-wide replication timing studies have suggested that mammalian chromosomes
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Publications
Replication program and genome instability
consist of megabase-scale domains of coordinated origin firing separated by large originless
transition regions. Here, we report a quantitative genome-wide analysis of DNA replication
kinetics in several human cell types that contradicts this view. DNA combing in HeLa cells
sorted into four temporal compartments of S phase shows that replication origins are spaced
at 40 kb intervals and fire as small clusters whose synchrony increases during S phase and
that replication fork velocity (mean 0.7 kb/min, maximum 2.0 kb/min) remains constant and
narrowly distributed through S phase. However, multi-scale analysis of a genome-wide
replication timing profile shows a broad distribution of replication timing gradients with
practically no regions larger than 100 kb replicating at less than 2 kb/min. Therefore, HeLa
cells lack large regions of unidirectional fork progression. Temporal transition regions are
replicated by sequential activation of origins at a rate that increases during S phase and
replication timing gradients are set by the delay and the spacing between successive origin
firings rather than by the velocity of single forks. Activation of internal origins in a specific
temporal transition region is directly demonstrated by DNA combing of the IGH locus in HeLa
cells. Analysis of published origin maps in HeLa cells and published replication timing and
DNA combing data in several other cell types corroborate these findings, with the interesting
exception of embryonic stem cells where regions of unidirectional fork progression seem
more abundant. These results can be explained if origins fire independently of each other but
under the control of long-range chromatin structure, or if replication forks progressing from
early origins stimulate initiation in nearby unreplicated DNA. These findings shed a new light
on the replication timing program of mammalian genomes and provide a general model for
their replication kinetics.
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