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Life Sciences

Molecular mechanisms underlying differential transcriptional regulation and function by thyroid hormone receptor isoforms

The research project is under the co-supervision of
WENG Jiemin (Biology, ECNU)  & Karine GAUTHIER (Biology, ENS de Lyon)

Thyroid hormone (T3) exerts a pleiotropic action on development and homeostasis. T3 acts on gene transcription by binding to the thyroid hormone receptors (TRs), including the TRα and TRβ isoforms. The transcriptional activity of TR is regulated by T3 binding which redefines the protein-protein interactions occurring at the receptor surface, in particular with cofactors necessary for their function.
Genome wide studies have recently highlighted that the T3 target gene repertories are very divergent in different tissues. This likely reflects specific expression and/or activity of the various TR isoforms in each given system. Moreover our recent results show that for some genes, in white adipose tissue (WAT), the regulation by T3 is TRβ selective even though TRα is also expressed. The questions we propose to tackle, using WAT as our model, is the following: to what extent are isoform selective regulation and the molecular mechanism responsible for this selectivity?

First we will try to identify new isoform-selective target genes in this tissue using mice in which either TRα or TRβ function has been abrogated. WAT T3 response will be determined by RNA massive sequencing. Comparison of the different genotypes will assess how many of the T3 targets are actually regulated in a TR isoform selective manner.

We will also test whether this isoform selectivity could rely on the different isoforms binding to- and being activated by- specific and different co-factors. To this end tagged TRα and TRβ proteins will be produced to test their ability to interact with a wide range of cofactors in presence or absence of T3 using pull down assay. If conclusive this in vitro study will be undertaken further in WAT.

This project is only possible thanks to the complementary expertise of the two labs in mouse genetics (ENS) and biochemistry (ECNU).


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Mise à jour le 18 avril 2012
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