CE12 - Génétique, génomique et ARN

CHROMAtin and GeNome evolutiON – CHROMAGNON

Submission summary

The essential role of chromatin in genome functional organization and expression has been largely ignored in evolutionary studies, since chromatin structure is much less traceable than coding sequences over evolutionary time. Recently, we developed a simple physical model of nucleosome occupancy based on the computation of the free energy cost of bending a DNA fragment of a given sequence from its natural curvature to the final superhelical structure around the histone core. In human, the model predicts the existence of nucleosome inhibitory energy barriers (NIEBs) corresponding to nucleosome-depleted regions, which constrain the positioning of 4-6 nucleosomes at their borders. The relevance of these predictions was corroborated by our analyses, which revealed that for over 38% of the human genome, in vivo nucleosome occupancy is encoded in the DNA sequence and form an evolutionary stable chromatin organization not subject to remodeling. Variations in nucleosome composition such as replacement of canonical histones with variants can further affect sequence accessibility. Our preliminary analysis indicates that the borders of murine NIEBs have specific positioned histone variant H3.3 nucleosomes- one of the most evolutionary conserved and ancient histones across all phyla.

Using sequence-encoded nucleosome positioning as a reference framework, CHROMAGNON aims to quantify chromatin constraints on evolution and natural selection and to identify novel fundamental conserved properties of chromatin. We plan to systematically analyze the substitution patterns at NIEB borders within groups of related vertebrate genomes (mouse/rat, chicken/turkey/duck and zebrafish/cave fish/medaka/- tilapia/platyfish) to assess the species specificity of stable chromatin-associated mutational patterns. Where experimental nucleosome positioning data are available, we will check to which extent intrinsic nucleosome organization around NIEBs remains valid in vivo across vertebrates. Repetitive mobile elements constitute nearly half of the human genome. Since we found that many (52%) Alu transposable elements were inserted flanking a NIEB, we will ask to which extent TEs are involved in the formation and maintenance of presumably conserved chromatin structures necessary for proper genome organization and expression. Next, using novel transgenic mouse models for H3.3 as well as knockout systems for chromatin-targeting H3.3 chaperones, we will determine to which extent nucleosome formation energy landscape at NIEB boundaries conditions H3.3 nucleosome formation, stability and chromatin histone exchange dynamics. To integrate the contributions from NIEB sequences, histone variants and remodeling factors on genome accessibility, we propose to develop an extended nucleosomal-array model and derive quantitative simulations of the relaxation dynamics of nucleosomal arrays in response to external perturbations by implementing kinetic Monte Carlo simulations. CHROMAGNON is thus an extremely interdisciplinary and innovative project that bridges evolutionary biology, chromatin structure and mathematical modeling to understand the function of the sequence-encoded structural organization of chromatin in higher eukaryotes.

This project involves multidisciplinary complementary expertise provided by three teams based in Lyon (France) that are all internationally recognized experts in their respective fields of research. Expertise required for the success of the project are provided by these teams and include bioinformatics and genomics (Audit-Vaillant/Volff), evolutionary biology (Volff), chromatin experimental biology (Padmanabhan) and physical modeling of the DNA polymer (Audit-Vaillant). The project will be also strongly dedicated to education through the hosting of postdoctoral researchers, a PhD candidate and master students, and the inclusion of the results in high-level master courses.

Project coordination

Benjamin AUDIT (LABORATOIRE DE PHYSIQUE DE L'ENS DE LYON)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LABORATOIRE DE PHYSIQUE LABORATOIRE DE PHYSIQUE DE L'ENS DE LYON
IGFL Institut de génomique fonctionnelle de Lyon
IGFL Institut de génomique fonctionnelle de Lyon

Help of the ANR 463,479 euros
Beginning and duration of the scientific project: February 2021 - 48 Months

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