Thermodynamics of DNA loops with long-range correlated structural disorder.

We study the influence of a structural disorder on the thermodynamical properties of 2D-elastic chains submitted to mechanical/topological constraint as loops. The disorder is introduced via a spontaneous curvature whose distribution along the chain presents either no correlation or long-range correlations (LRC). The equilibrium properties of the one-loop system are derived numerically and analytically for weak disorder. LRC are shown to favor the formation of small loop, larger the LRC, smaller the loop size. We use the mean first passage time formalism to show that the typical short time loop dynamics is superdiffusive in the presence of LRC. Potential biological implications on nucleosome positioning and dynamics in eukaryotic chromatin are discussed

La transformation en ondelettes continue : un microscope mathématique adapté à l'étude des propriétés d'invariance d'échelle et de corrélations à longue portée des séquences d'ADN

Depuis le début des années 90, l'intérêt des mathématiciens, physiciens et informaticiens pour l'analyse statistique des séquences d'ADN n'a pas cessé de croître. En effet, les immenses progrès de la biologie moléculaire et les grands projets de séquençage ont révélé l'extraordinaire complexité des génomes. Afin de mieux comprendre l'organisation et l'évolution des génomes, il est apparu nécessaire d'introduire de nouveaux concepts et de nouvelles techniques d'analyse du signal. Ainsi la possibilité que les séquences d'ADN présentent des propriétés d'invariance d'échelle associées à l'existence de corrélations à longue portée (CLP) a été le sujet d'une longue controverse. La raison principale de ce malentendu est le caractère non stationnaire des séquences d'ADN résultant de l'hétérogénéité de composition des génomes. Cette observation nous a conduit à proposer l'utilisation de la transformation en ondelettes continue (TO) comme outil naturel d'analyse des séquences d'ADN : par un choix adéquat de l'ondelette analysatrice, on peut s'affranchir de la "structure mosaïque" de ces séquences et quantifier l'existence de CLP associées à des propriétés d'invariance d'échelle monofractales. L'exploration de séquences d'ADN du génome humain sous l'optique du microscope TO, nous a permis de démontrer l'existence de CLP dans les séquences exoniques (codantes pour les protéines) comme dans les séquences introniques (non codantes), remettant par là en cause les différentes interprétations de ces corrélations à l'aide de modèles de dynamique évolutive (plasticité) des génomes. En profitant de la disponibilité de génomes complets (levure, E. coli,...) et en utilisant différentes tables expérimentales associant des di- ou tri- nucléotides à des grandeurs de nature structurelle (courbure, flexibilité), nous avons montré récemment qu'il est possible d'extraire des séquences d'ADN des informations sur l'organisation spatiale et dynamique de la double hélice dans les cellules via l'interaction avec certaines protéines de structure telles que les histones pour la formation du nucléosome eucaryote. En particulier, l'existence et la nature des CLP jusqu'à des distances de l'ordre de 3 104 nucléotides dans certains profils de courbure et/ou de flexibilité locales permettent de diagnostiquer la présence de nucléosomes dans les génomes étudiés. L'observation de certaines CLP dans tous les organismes eucaryotes ainsi que dans les organismes des deux autres règnes (eubactéries et archaeabactéries) suggère fortement que ces corrélations pourraient être essentielles aux phénomènes de condensation-décondensation de la chromatine en relation avec les processus de réplication, transcription et division cellulaire

Open chromatin encoded in DNA sequence is the signature of ‘master’ replication origins in human cells

For years, progress in elucidating the mechanisms underlying replication initiation and its coupling to transcriptional activities and to local chromatin structure has been hampered by the small number (approximately 30) of well-established origins in the human genome and more generally in mammalian genomes. Recent in silico studies of compositional strand asymmetries revealed a high level of organization of human genes around 1000 putative replication origins. Here, by comparing with recently experimentally identified replication origins, we provide further support that these putative origins are active in vivo. We show that regions ∼300-kb wide surrounding most of these putative replication origins that replicate early in the S phase are hypersensitive to DNase I cleavage, hypomethylated and present a significant enrichment in genomic energy barriers that impair nucleosome formation (nucleosome-free regions). This suggests that these putative replication origins are specified by an open chromatin structure favored by the DNA sequence. We discuss how this distinctive attribute makes these origins, further qualified as ‘master’ replication origins, priviledged loci for future research to decipher the human spatio-temporal replication program. Finally, we argue that these ‘master’ origins are likely to play a key role in genome dynamics during evolution and in pathological situations

3D reconstruction and comparison of shapes of DNA minicircles observed by cryo-electron microscopy

We use cryo-electron microscopy to compare 3D shapes of 158 bp long DNA minicircles that differ only in the sequence within an 18 bp block containing either a TATA box or a catabolite activator protein binding site. We present a sorting algorithm that correlates the reconstructed shapes and groups them into distinct categories. We conclude that the presence of the TATA box sequence, which is believed to be easily bent, does not significantly affect the observed shapes

Mechanics of the IL2RA Gene Activation Revealed by Modeling and Atomic Force Microscopy

Transcription implies recruitment of RNA polymerase II and transcription factors (TFs) by DNA melting near transcription start site (TSS). Combining atomic force microscopy and computer modeling, we investigate the structural and dynamical properties of the IL2RA promoter and identify an intrinsically negative supercoil in the PRRII region (containing Elf-1 and HMGA1 binding sites), located upstream of a curved DNA region encompassing TSS. Conformational changes, evidenced by time-lapse studies, result in the progressive positioning of curvature apex towards the TSS, likely facilitating local DNA melting. In vitro assays confirm specific binding of the General Transcription Factors (GTFs) TBP and TFIIB over TATA-TSS position, where an inhibitory nucleosome prevented preinitiation complex (PIC) formation and uncontrolled DNA melting. These findings represent a substantial advance showing, first, that the structural properties of the IL2RA promoter are encoded in the DNA sequence and second, that during the initiation process DNA conformation is dynamic and not static

Risques et adaptation nutritionnelle en cancérologie

This article starts with a presentation of Caycedian Sophrology. We then evaluate its impact on stress reduction through a questionnaire on a students’ population. It appears that stress level increases between the two sessions in the control group while it decreases in the experimental group

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

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

Modeling the Functional Coupling between 3D Chromatin Organization and Epigenome

International audienceIn this chapter, the authors review their efforts to understand the functional coupling between the three-dimensional (3D) dynamical organization of chromatin and the 1D segmentation of genome into active and inactive domains using polymer and statistical physics modeling. They discuss how polymer modeling allows them to better understand the coupling between epigenome and 3D chromosome organization. The observed correlations between epigenome and contactome suggest the existence of epigenomic-specific mechanisms playing major roles in chromatin folding. The authors develop several methods to investigate the behavior of the block copolymer model of chromatin. In the context of epigenomics, the nano-reactor hypothesis naturally introduces a functional coupling between 3D organization and 1D epigenomic state. In order to progress toward a quantitative description of this 1D–3D coupling, a correct parameter inference would require experiments that can record the large-scale dynamics of both the 1D and 3D organization, during the establishment and the maintenance stages, in both wild-type and mutant backgrounds