Description du projet
Une feuille de route pour percer les secrets de la régulation cellulaire
Les facteurs de transcription (FT) jouent un rôle important dans le monde de la régulation cellulaire, orchestrant l’expression des gènes, vitale pour l’identité et la santé des cellules. La manière dont les FT coopèrent pour activer la transcription demeure toutefois une énigme. Dans ce contexte, le projet TFCoop, financé par le CER, va étudier des centaines de milliers de perturbations des FT dans les réseaux concernés. Plus précisément, les chercheurs se proposent mettre en lumière les règles organisationnelles qui régissent la coopération des FT. En s’appuyant sur des techniques innovantes telles que l’optogénétique et la génomique à molécule unique, TFCoop entend décoder le schéma génétique qui sous-tend les identités cellulaires. Une réussite pourrait révolutionner la médecine régénérative, offrant des perspectives inédites de manipulation cellulaire.
Objectif
Transcription Factors (TFs) are critical regulators of many essential cellular functions such as the acquisition of cell identities in healthy tissues and their dysregulation in disease. Transcriptional activation of a gene typically requires the cooperative binding of multiple TFs, that subsequently recruit various additional cofactors. Genomics has enabled the generation of a near-complete annotation of the cis-regulatory elements and TFs binding them across cell types. Yet, the precise function of each TF in the process and how these functionalities are assembled to activate transcription is an important open question. Here we postulate that despite strong cell-type specificity, the formation of TF cooperativity modules on DNA relies on general principles that are shared across cell-types. In TFCoop we propose to formalise these organizational rules by probing the effect of hundreds of thousands of perturbations of individual TFs on the regulatory activity of their network. We will apply time-resolved nuclear depletion using optogenetics in parallel for multiple TFs of two related networks, and contrast the primary effects of their depletion genome-wide. In a complementary approach, we will develop a reductionist system to study the function of tens of thousands of individual or controlled combinations of TF motifs when inserted into the genome. We will leverage the unique properties of single molecule genomics to measure the contribution of each TF to the activity of multiple components of the regulatory system, across multiple loci simultaneously. This will be followed by factor analysis and deep learning to integrate this large collection of primary effects of TF perturbation and identify the general principles of their assembly into cooperativity networks. Upon success of the project, the resulting models will unlock the understanding of the genetic encoding of cellular identities and allow their manipulation for regenerative medicine.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régime de financement
HORIZON-ERC - HORIZON ERC GrantsInstitution d’accueil
69117 Heidelberg
Allemagne