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KRAB/KAP1-mediated gene regulation in mammalian physiology and human diseases

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.

Field of science

  • /medical and health sciences/basic medicine/pathology
  • /medical and health sciences/basic medicine/physiology/homeostasis
  • /natural sciences/chemical sciences/inorganic chemistry/inorganic compounds
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/genetics and heredity/genome
  • /medical and health sciences/basic medicine/physiology

Call for proposal

ERC-2010-AdG_20100317
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Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Address
Batiment Ce 3316 Station 1
1015 Lausanne
Switzerland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 499 996,03
Principal investigator
Didier Trono (Prof.)
Administrative Contact
Caroline Vandevyver (Ms.)

Beneficiaries (1)

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Switzerland
EU contribution
€ 2 499 996,03
Address
Batiment Ce 3316 Station 1
1015 Lausanne
Activity type
Higher or Secondary Education Establishments
Principal investigator
Didier Trono (Prof.)
Administrative Contact
Caroline Vandevyver (Ms.)