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Découverte par l'équipe de Laurent Viriot
Functional genomics of nuclear receptors - Activity
Role and mechanisms of action of thyroid hormone receptors in normal and pathological development.
Thyroid hormone is playing a major role in the development and tissue homeostasis in the Vertebrates. Their physiological effects are mediated through binding to nuclear receptors which are transcription factors. In mammals two genes respectively THRA and THRB encode several isoforms of the receptors TRa and TRb. Our group is interested in dissecting the respective functions of these isoforms in the development of the mouse by creating mutants with targeted mutations in the genes encoding the receptors. From this work we could conclude that the TRa receptor plays a major role during the neonatal period in inducing the maturation of several tissues like bone, brain, intestine, and spleen erythropoieisis. For example, in the neonate intestine TRa directly activates proliferation of epithelial cell progenitors through the transcriptional activation of the b-catenin gene. We also showed that before birth, the naturally unliganded forms of TRa control the functional development of the heart by repressing transcription of cardiac genes and slowing down heart rate.
The present projects aim at identifying target genes regulated by TR isoforms during development and understanding how TR isoforms modify chromatin structure on these genes. This work is being extended to identify the direct role of TR isoforms in the development of some specific human tumors.
Molecular bases of development of embryonic stem cells.
Embryonic stem cells (ES cells) are pluripotent cells present at very early stages of embryonic development. Our group has been pioneer in isolating ES cells from chicken embryo. This model is useful for addressing the question of the mechanisms controlling pluripotency and commitment to differentiation of these cells at the early stages of embryonic development. Our aim is to identify genes that are specifically expressed in ES cells and which might control their development. One such gene ENS-1 encodes a coiled-coil protein that interacts with proteins involved in chromatin organization. Using high throughput functional genomics we isolated a series of genes whose expression provides a signature for pluripotent ES cells or committed cells. Some of these genes directly control pluripotency. The role of these genes in early embryonic development is being investigated by manipulating their expression directly in the living embryo.
