Thesis offer: Searching for the target genes of thyroid hormone nuclear receptors at genome wide scale.
Supported by the ERGO European program and INRA.
Thyroid hormone (T3) regulates a number of important physiological and developmental processes. The cellular response to T3 is cell-type specific: for example, T3 promotes the growth of neuronal axons, regulates glucose metabolism in hepatocytes and activates thermogenic biochemical reactions in brown adipocytes. T3 acts directly on transcription by binding nuclear receptors called TRs present in all these cell types. Upon T3 binding DNA-bound TRs undergo a structural transition which favors the recruitment of coactivators, which enhancesthe transcription of neighboring genes. The repertoire of TRs target genes in the different cell types are currently, for a large part, unknown.
Some environmental chemicals are suspected to interfere with T3 function, and to exert in this way a long-term toxicity. The associated risk is however difficult to address on rodent models without a complete knowledge of T3/TRs target genes. Within the ERGO project, the task of the IGFL group “functional genomics of thyroid hormone receptors” is to identify these genes in the cell types relevant to T3 action in mice, and to test the capacity of genomic analysis to detect perturbation of T3 signaling by model compounds.
The thesis program will be focused on the identification of T3 target genes in the brown adipocytes. The analysis will be based on a comparative analysis between transgenic mice, in which the T3 response of brown adipocytes is lost, and control mice. The thermogenesis capacity of the mice will be challenged by exposing them to various temperatures. Gene expression (RNAseq) and chromatin occupancy by TRs (ChipSeq) will be analyzed at genome-wide scale, after T3 stimulation. Finally, a novel in vitro assay will be used to address in a systematic manner the transactivation capacity of the genomic fragments bound by TRs. After full characterization of the T3/TRs target genes in adipocytes, the influence of chemicals with putative disruptor capacity on their expression will be addressed.
This project will increase basic knowledge about the mechanisms of action of T3. Together with other outcomes of the ERGO project, it will allow improving the European guidelines to detect thyroid disruptors.
The recruited candidate should have a general knowledge of physiology and molecular biology. She/he should be highly motivated to learn how to produce and analyze genomic data in a physiologically relevant model.
Frederic Flamant Frederic.firstname.lastname@example.org
Functional genomics of thyroid hormone signaling group
Institut de Génomique Fonctionnelle de Lyon
Ecole Normale Supérieure de Lyon
46 allée d’Italie 69364 Lyon CEDEX07
Tel: 00 (33) 4 26 73 13 32
For more information on the Functional Genomics of Thyroid Hormone Signaling Group please click here