Our research focuses on understanding how higher-order chromatin organization and epigenetic mechanisms are involved in controlling gene expression in mammals in both physiological and pathological contexts. Our research program consists in two interconnected projects:
1.Higher-order chromatin organization and gene regulation at imprinted loci.
Our group contributed to the development of the Chromosome Conformation Capture (3C) technologies by improving the sensitivity of the 3C assay (3C-qPCR method) (Hagège et al., 2007 Nature Protocols 2, 1722). In recent years, we investigated 3D chromatin organization in vivo at the imprinted Igf2/H19 gene locus and discovered an H19 antisense RNA that is overexpressed in human breast tumors (collaboration with Eric Adriaenssens, Lille) and leads to transcriptional activation of Igf2 through activation of a novel promoter (collaboration with Luisa Dandolo, Paris) (Tran et al., 2012 PLos ONE 7, e37923). We also contributed to demonstrate that, at this locus, an epigenetic switch in chromatin organization controls a switch in the expression of Igf2 and H19 genes (Court et al., 2011 Nucl. Acids Res. 39, 5893), thus providing an instance of a putative chromatin-based allosteric mechanism (Lesne et al. 2015 J. Phys.Condens. Matter 27, 064114).
2.Dynamics and higher-order organization of the mammalian chromatin.
Using the 3C-qPCR method, we showed that gene-rich loci display modulated contact frequencies (Court et al., 2011 Genome Biol. 12, R42). After initiating an interdisciplinary collaboration with physicists, we showed that this modulation can be described by polymer models as if the mammalian chromatin was folded statistically into a helix shape (statistical helix model, see figure).
We then showed that distinct principles of polymer physics govern chromatin dynamics in mouse and Drosophila topological domains (collaboration with Giacomo Cavalli, Montpellier) (Ea et al., 2015 BMC Genomics 16, 607).
Finally, we developed a novel method for genome-wide analyses of sequences associated to large ribonucleoproteic (RNP) complexes (HRS-seq method) and showed that active chromosomal compartments are associated to such large RNP complexes including nuclear bodies (Baudement et al., Genome Res.28:1733-1746).
Our project now lies at the frontiers between experimental biology, bioinformatics and modeling methods coming from theoretical physics.
We are using the HRS-seq method to perform genomic profiling of sequences involved in higher-order chromatin organization through contacts with nuclear bodies.
This methodology is used in physiological or pathological contexts (spinal muscular atrophy patients, cancer cells...) to identify novel regulatory elements involved in the coordination of gene expression and the maintenance of cell identity in mammals (project supported by the AFM-Téléthon).