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Accueil > Départements > Biologie des Génomes > Daan NOORDERMEER : Dynamique de la Chromatine



  • P. J. Fabre, M. Leleu, B. H. Mormann, L. Lopez-Delisle, D. Noordermeer, L. Beccari, et D. Duboule, « Large scale genomic reorganization of topological domains at the HoxD locus », Genome Biology, vol. 18, nᵒ 1, p. 149, 2017.
    Résumé : BACKGROUND: The transcriptional activation of HoxD genes during mammalian limb development involves dynamic interactions with two topologically associating domains (TADs) flanking the HoxD cluster. In particular, the activation of the most posterior HoxD genes in developing digits is controlled by regulatory elements located in the centromeric TAD (C-DOM) through long-range contacts. RESULTS: To assess the structure-function relationships underlying such interactions, we measured compaction levels and TAD discreteness using a combination of chromosome conformation capture (4C-seq) and DNA FISH. We assessed the robustness of the TAD architecture by using a series of genomic deletions and inversions that impact the integrity of this chromatin domain and that remodel long-range contacts. We report multi-partite associations between HoxD genes and up to three enhancers. We find that the loss of native chromatin topology leads to the remodeling of TAD structure following distinct parameters. CONCLUSIONS: Our results reveal that the recomposition of TAD architectures after large genomic re-arrangements is dependent on a boundary-selection mechanism in which CTCF mediates the gating of long-range contacts in combination with genomic distance and sequence specificity. Accordingly, the building of a recomposed TAD at this locus depends on distinct functional and constitutive parameters.
    Mots-clés : CHRODY, Chromatin organization, CTCF, DBG, Enhancer, Gene regulation, Hox, Limb development, Regulatory landscape, TAD, Topologically associating domains.

  • E. Thierion, J. Le Men, S. Collombet, C. Hernandez, F. Coulpier, P. Torbey, M. Thomas-Chollier, D. Noordermeer, P. Charnay, et P. Gilardi-Hebenstreit, « Krox20 hindbrain regulation incorporates multiple modes of cooperation between cis-acting elements », PLoS genetics, vol. 13, nᵒ 7, p. e1006903, 2017.
    Résumé : Developmental genes can harbour multiple transcriptional enhancers that act simultaneously or in succession to achieve robust and precise spatiotemporal expression. However, the mechanisms underlying cooperation between cis-acting elements are poorly documented, notably in vertebrates. The mouse gene Krox20 encodes a transcription factor required for the specification of two segments (rhombomeres) of the developing hindbrain. In rhombomere 3, Krox20 is subject to direct positive feedback governed by an autoregulatory enhancer, element A. In contrast, a second enhancer, element C, distant by 70 kb, is active from the initiation of transcription independent of the presence of the KROX20 protein. Here, using both enhancer knock-outs and investigations of chromatin organisation, we show that element C possesses a dual activity: besides its classical enhancer function, it is also permanently required in cis to potentiate the autoregulatory activity of element A, by increasing its chromatin accessibility. This work uncovers a novel, asymmetrical, long-range mode of cooperation between cis-acting elements that might be essential to avoid promiscuous activation of positive autoregulatory elements.
    Mots-clés : Animals, Body Patterning, CHRODY, Chromatin, DBG, Early Growth Response Protein 1, Enhancer Elements, Genetic, Gene Expression Regulation, Developmental, Mice, Knockout, Mutation, Regulatory Elements, Transcriptional, Rhombencephalon, Sequence Homology, Nucleic Acid.


  • M. Matelot et D. Noordermeer, « Determination of High-Resolution 3D Chromatin Organization Using Circular Chromosome Conformation Capture (4C-seq) », Methods in Molecular Biology (Clifton, N.J.), vol. 1480, p. 223-241, 2016.
    Résumé : 3D chromatin organization is essential for many aspects of transcriptional regulation. Circular Chromosome Conformation Capture followed by Illumina sequencing (4C-seq) is among the most powerful techniques to determine 3D chromatin organization. 4C-seq, like other modifications of the original 3C technique, uses the principle of "proximity ligation" to identify and quantify ten thousands of genomic interactions at a kilobase scale in a single experiment for predefined loci in the genome.In this chapter we focus on the experimental steps in the 4C-seq protocol, providing detailed descriptions on the preparation of cells, the construction of the circularized 3C library and the generation of the Illumina high throughput sequencing library. This protocol is particularly suited for the use of mammalian tissue samples, but can be used with minimal changes on circulating cells and cell lines from other sources as well. In the final section of this chapter, we provide a brief overview of data analysis approaches, accompanied by links to publicly available analysis tools.
    Mots-clés : 3D chromatin organization, 4C-seq, CHRODY, Chromatin compartmentalization, Chromatin loops, Circular Chromosome Conformation Capture, DBG, DNA interactions, High-throughput sequencing, nuclear organization.
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Publications majeures avant 2016

- Vieux-Rochas, M., Fabre, P.J., Leleu, M., Duboule, D. and Noordermeer, D. (2015) Clustering of mammalian Hox genes with other H3K27me3 targets within an active nuclear domain. PNAS 112, 4672-4677

- Ghavi-Helm, Y., Klein, F., Pakozdi, T., Ciglar, L., Noordermeer, D., Huber, W. and Furlong, E.E.M. (2014) Enhancer loops appear stable during development and are associated with paused polymerase. Nature 512, 96-100

- Noordermeer, D., Leleu, M., Schorderet, P., Joye, E., Chabaud, F. and Duboule, D. (2014) Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci. eLife 3, e02557

- Andrey, G., Montavon, T., Mascrez, B., Gonzalez, F., Noordermeer D., Leleu, M., Trono, D., Spitz, F. and Duboule D. (2013) A functional switch between topological domains underlies HoxD genes collinearity in limbs. Science 340, 1195

- Coléno-Costes, A., Jang, S.M., de Vanssay, A., Rougeot, J., Bouceba, T., Randsholt, N.B., Gibert, J.M., Le Crom, S., Mouchel-Vielh, E., Bloyer, S. and Peronnet, F. (2012) New partners in regulation of gene expression : the enhancer of Trithorax and Polycomb Corto interacts with methylated ribosomal protein l12 via its chromodomain. PLoS Genet 8, e1003006

- Debat, V., Bloyer, S., Faradji, F., Gidaszewski, N., Navarro, N., Orozco-Terwengel, P., Ribeiro, V., Schlötterer, C., Deutsch, J.S. and Peronnet, F. (2011) Developmental stability : a major role for cyclin G in drosophila melanogaster. PLoS Genet 7, e1002314

- Noordermeer, D., Leleu, M., Splinter, E., Rougemont, J., De Laat, W. and Duboule, D. (2011) The dynamic architecture of Hox gene clusters. Science 334, 222-225

- Noordermeer, D., De Wit, E., Klous, P., Van De Werken, H., Simonis, M., Lopez-Jones, M., Eussen, B., De Klein, A., Singer, R. H. and De Laat, W. (2011) Variegated gene expression caused by cell-specific long-range DNA interactions. Nature Cell Biology 13, 944-951

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