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Regulation of transcription

Regulation of transcription

DEPARTMENT

Integrated structural biology

TEAM LEADER

Albert WEIXLBAUMER

The blueprint of all cellular organisms is stored in the form of genes in their DNA. This genetic information needs to be accessed, retrieved, and decoded in a process called gene expression. Gene expression needs to occur in a precisely controlled manner in order to convert the genotype of an organism to the phenotype of an organism. Erroneous gene expression on the other hand has severe consequences. The goal in our team is to obtain a detailed and mechanistic understanding of the cellular machineries, which carry out gene expression. This is important for several reasons:
1)    Gene expression plays a fundamental role and affects almost every aspect of biology. A lot of our motivation to understand gene expression is therefore driven by curiosity.
2)    The majority of drugs against human pathogens target the enzymes involved in gene expression. The better you understand your target, the better you understand how to improve drugs or design new ones.
3)    Many human pathologies including cancers, neurodevelopmental disorders or autoimmune diseases are the result of misregulated gene expression. A prerequisite to developing effective strategies against a specific disease, however, is to understand the underlying process in as much detail as possible.
The first step of gene expression is to transcribe DNA into RNA and it is carried out by a universally conserved enzyme called RNA polymerase. The DNA transcript, called messenger RNA or mRNA, is subsequently translated to protein by another universally conserved molecular machine called the ribosome. Many organisms including humans need to process the mRNA first before it can be translated.
Gene expression is tightly controlled at each step but transcription is arguably one of the most important targets for regulatory processes.  One focus of research in our team is to understand how proteins called transcription factors are able to regulate RNA polymerase and therefore modulate the transcription of DNA to RNA. Transcription is often directly regulated by RNA and we would like to understand how regulatory RNA elements affect RNA polymerase. Finally, the enzymes carrying out gene expression do not operate in isolation. They are often organized in larger, supramolecular assemblies. In these assemblies their functions are coordinated and new functions can emerge. We are increasingly addressing this aspect and study how RNA polymerase is organized along other key enzymes in higher order structures.
We use bacterial or eukaryotic models and combine molecular biology, and biochemistry with X-ray crystallography and single particle Cryo-EM to describe these processes at the molecular level.

Current projects

  • Structural investigations on transcription factors bound to RNA polymerase elongation complexes in states of transcriptional pausing
  • Non-coding RNAs modulating RNA polymerase elongation complexes
  • Structural basis for the coupling of transcription and translation
  • Interplay between DNA topology and transcription
  • Coupling of transcription and mRNA processing (Project leader Clément CHARENTON)

Collaborations and networks

  • We work with Terence STRICK (Ecole Normale Supérieure de Paris) to combine structural studies with single molecule techniques to elucidate fundamental processes in transcription regulation
  • We work with Olivier ESPÉLIE (College de France) and Valérie LAMOUR (IGBMC) to study the interplay between transcription and DNA topology
  • We work in a collaborative atmosphere with different teams at IGBMC

Funding and partners

  •    ERC
  •    ANR  
  •    Fondation Bettencourt-Schueller
  •    Ligue contre le Cancer
  •    Programme d'investissement avenir

Awards and recognitions

  • ATIP-Avenir 2014
  • ERC Starting Grant 2015
  • Prix Guy Ourisson 2018
  • Coups d’élan pour la recherche française 2021

Publications

Integrated structural biology - Cancer research