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Home page > Research Groups > Thierry FORNE - Genomic Organization and Epigenetic Control

Thierry FORNE - Genomic Organization and Epigenetic Control

Genome sequencing reveals that the patterns of development in mammals depend essentially on proper spacio-temporal regulation of highly conserved genes. We focus on two steps of the gene expression pathway: the epigenetic regulation of nuclear genomic architecture and the co-post-transcriptional regulation. We use mouse imprinted genes as model systems to determine how these two steps are integrated to lead to harmonious gene expression and how they become altered in pathological situations such as cancer.

Gene expression involves regulatory elements, such as enhancers or insulators, whose activities are often controlled across several hundred of kilobase-pairs (kb) by epigenetic modifications. Moreover, in mammals, genes are often clustered in specific portions of the chromosomes, and regulatory elements are then shared between several genes of the cluster. This is the case for most of the so-called imprinted genes, the expression of which depends on the parental origin of the alleles. Therefore, to understand how gene expression is coordinated within the clusters and how enhancers and insulators work, it is crucial to understand how the mammalian genome is organized at the supranucleosomal scale (i.e. for genomic distances encompassing ten to few hundreds kb). Our projects aim to unravel the dynamics and higher-order organization of the mammalian chromatin.

Our laboratory contributed to the development of the Chromosome Conformation Capture (3C) technologies by improving the quantification of the interaction frequencies between distant chromatin regions (3C-qPCR method) (Hagège et al., 2007 Nature Protocols 2, 1722). We applied this method to analyse both the Dlk1/Gtl2 and Igf2/H19 imprinted loci and we identified several specific looping interactions thus bringing original insights into the complex mechanisms of gene regulation at these two loci (Braem et al., 2008 J. Biol. Chem. 283, 18612), including the identification of novel non-coding RNAs (Court et al., 2011 Nucl. Acids Res. 39, 5893-5906 ; Tran et al., 2012 PLos ONE 7, e37923). We also measured, in transcriptionally active mouse nuclei and at several loci, the frequencies of random collisions between genomic sites separated by increasing distances. By fitting appropriate models issued from polymer physics to our experimental data, we have provided a first estimate of the basic biophysical parameters and statistical shape of the mammalian chromatin at the supranucleosomal scale (Court et al., 2011 Genome Biol. 12: R42) (Statistical Helix Model, see Figure).

Our project now lies at the frontiers between experimental biology, bioinformatics and models from theoretical physics (see « Bioinformatics et Modeling » thumb) around two main themes: (i) a detailed study of the dynamics and basic higher order organisation of the chromatin in several genetic and epigenetic contexts (Ea et al., en preparation) (ii) locus-specific and genome-wide identifications of regulatory elements involved in higher-order chromatin organisation associated with tissue-specific gene expression and cell identity in mammals.


Institut de Génétique Moléculaire de Montpellier
CNRS-UMR 5535 - 1919, Route de Mende - 34293 Montpellier  Cedex 5
FRANCE
(+33) 04 34 35 96 01