Objective This project aims at exploring the roles or KRAB/KAP1-mediated gene regulation in mammalian physiology and the possible impact of its dysfunctions on human health. The proper control of gene expression is paramount to all biological events, and is orchestrated through a sophisticated balance of activating and repressing influences. The mouse and human genomes contain around four hundred genes encoding KRAB-containing zinc finger proteins (KRAB-ZFPs), a family of tetrapod-restricted sequence-specific DNA-binding transcriptional repressors. Even though these KRAB-ZFPs represent the single largest group of transcriptional regulators encoded by higher vertebrates, their functions remain largely unknown. Nevertheless, it has been established that they share an essential cofactor, the histone methyltransferase- and histone deacetylase-recruiting KAP1, and act by triggering the formation of heterochromatin. KAP1 is ubiquitous, and KRAB-ZFPs are present in most if not all cells, albeit along distinctly cell type-, stage- and state-specific patterns, suggesting that KRAB/KAP1 gene regulation influences a very large number of physiological events. A few years ago, we launched a program aimed at addressing this hypothesis through a combination of genetic, functional and molecular studies focused on two paradigmatic organs, the lympho-hematopoietic system and the liver. Our preliminary results confirm that KRAB/KAP1-mediated transcriptional control is a master regulator of mammalian homeostasis. Accordingly, we now propose to dissect the regulatory networks orchestrated by KAP1 and KRAB-ZFPs in these two systems, to identify their gene targets and the mechanisms of their control, and to probe their possible implication in human pathologies targeting these organs. Fields of science natural scienceschemical sciencesinorganic chemistrytransition metalsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicinepathologynatural sciencesbiological sciencesgeneticsgenomesmedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS4 - ERC Advanced Grant - Physiology, Pathophysiology and Endocrinology Call for proposal ERC-2010-AdG_20100317 See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Host institution ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE EU contribution € 2 499 996,03 Address BATIMENT CE 3316 STATION 1 1015 Lausanne Switzerland See on map Region Schweiz/Suisse/Svizzera Région lémanique Vaud Activity type Higher or Secondary Education Establishments Principal investigator Didier Trono (Prof.) Administrative Contact Caroline Vandevyver (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE Switzerland EU contribution € 2 499 996,03 Address BATIMENT CE 3316 STATION 1 1015 Lausanne See on map Region Schweiz/Suisse/Svizzera Région lémanique Vaud Activity type Higher or Secondary Education Establishments Principal investigator Didier Trono (Prof.) Administrative Contact Caroline Vandevyver (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
