Epi-transcriptomics

RNP multiscale organization, phase transitions, and the adaptive regulations of gene expression during early development.

 

 

Our laboratory is interested in understanding how ribonucleoprotein (RNP) subcellular organization regulate RNA expression to carry a genetic information that is coordinated to the cell lineage and adapted to the cellular environment. Our research combines multidisciplinary approaches including biophysical characterization of RNP states and phase transitions in vivo, genetic and synthetic biology approaches to manipulate these RNP states, live imaging of RNA using fluorescent reporters, transcriptomics and proteomics coupled to system biology analysis of RNP droplets, hydrogels and aggregates. Models include C. elegans germline and embryo early development, as well as mammal cells in culture. Ultimately, we aim at providing a new conceptual framework to tackle the deregulations in RNP organization and RNA expression that can lead to evolutionary diseases such as degenerative diseases and cancer.

 

Figure 1: RNP coassemblies in C. elegans germline. Successive magnifications, scaling from C. elegans nematode to cytoslic RNP granules. Two sub-types of granules, germ granules in red and germline P-bodies (grPB) in green, are visualized by fluorescence in live animals (Dash lines delineate nuclei (N)).

Large coassemblies of nucleic acids and proteins are a common feature of gene expression pathways. Chromatin and ribonucleoproteins (RNPs) condense and compartmentalize thousands of molecules. We and others have previously shown how ribonucleoproteins (RNPs) can exist under different states: soluble, liquid droplets, hydrogels, or solid pathological aggregates. Within cells, RNPs undergo phase transitions between these states in response to environmental and developmental cues. These phase transitions coordinate the exchange of RNAs, their local concentrations, and their subcellular distributions. Thus, RNP multiscale organization and phase transitions allows for the adaptive regulations of RNA expression during early development.

Figure 2. RNP phase transitions during development. (A-C) Schematic representation of RNP molecular behavior. (A’-C’) Confocal images of corresponding phase transitions for grPB components. Scale bar 5 um. During active oogenesis RNPs do not coassemble (A), and diffuse in the cell (A’). Following oogenesis arrest RNPs interact in a dynamic manner (B), and condense into grPB liquid droplets (B’). cgh-1/ddx6 RNA helicase loss of function induces a stable polymerization (C), which results in solidification into ’crystal like’ square sheets (C’). These three states share numerous components, including repressed mRNPs. (D) Viscous droplets segregate mRNPs during oocyte quiescence, dissolution mixes mRNPs during oocyte activation and condensation into highly fluid droplets asymmetrically distribute mRNPs for the onset of the embryonic program.

 

 

Figure 3: Model for RNP coassemblies.From left to right: (1) At the single mRNP scale mRNAs and proteins interact through stereospecific interactions. (2) Multiple mRNPs interact with each other through RNA multivalency and the interactions between disordered regions containing polyQ peptides. (3) As a result of these dynamic interactions, RNPs condense into semi-liquid droplets that can reach 10 m in size. Note that droplets themselves are compartmentalized.

 

Our primary goal is to understand how RNP phase transitions integrate developmental and environmental cues to control RNA fate, with the following 3 main axes of research:

  1. Characterizing the material properties of RNP superassemblies (liquid RNP droplets, semi-liquid hydrogels, solid pathological aggregates...), and manipulating the key parameters controlling RNP phase transitions between these various states.
  2. Dissecting how RNP states and phases transitions control the fate of RNA molecules.
  3. Mapping how the transcriptome 3D organization changes during development and in response to the environment.
Last publications

Modifiers of solid RNP granules control normal RNP dynamics and mRNA activity in early development. - 2015 - The Journal of cell biology - 211 P703-16 - Hubstenberger A, Cameron C, Noble SL, Keenan S, and Evans,TC

Translation repressors, an RNA helicase, and developmental cues control RNP phase transitions during early development. - 2013 - Developmental cell - 27 P161-73 - Hubstenberger A, Noble SL, Cameron C, and Evans,TC

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Hubstenberger Arnaud
Group Leader

2017 Young team leader starting grant. ATIP-AVENIR (CNRS-INSERM)

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JOB OFFERS

    May 2017 - A. Hubstenberger Team
   1 POST-DOC position - 2 years

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CNRS UMR7277, Inserm U1091, UNS Université Nice Sophia Antipolis
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