iiinova — where your digital self keeps evolving

(7/7) This work was done despite the unprecedented attack by the Argentine government on basic science and the University Educational System. We thank our National and International colleagues.

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(6/7) Collectively, our work reconciles contradicting reports regarding GR stoichiometry during import by demonstrating that both monomers and dimers translocate, albeit through distinct mechanisms.

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(5/7) While GR monomers rely exclusively on passive diffusion, GR dimers also utilize the microtubule-dynein machinery for active transport.

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(4/7) Using the two-color pCF approach, we found evidence for dimer formation during translocation. In fact, both dimers and monomers can translocate but use different strategies.

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(3/7) As a transcription factor, activated GR must travel into the nucleus to regulate genes. However, some questions remain about how GR reaches the nuclear compartment: 1) Does it translocate as a monomer or as a dimer? 2) Does it reach the nuclear pore aided by the microtubule network?

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(2/7) In this work, we investigate how GR translocates from the cytoplasm to the nucleus, using a fluorescence microscopy technique called pair correlation function (pCF)

(1/7)🚨Pre-print alert!🚨 Happy to share our latest work on glucocorticoid receptor (GR) biology, led by Cecilia De Rossi from the Valeria Levi lab and Presman lab www.biorxiv.org/content/10.6...

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Too many people to thank, but all this journey would not have been possible without the mentorship of Adali Pecci, Valeria Levi, the Gordon Hager lab, and crucial collaborations with the Estébanez-Perpiñá team, who joined us in this fight. Special thanks to my PhD student, Agustina!

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In summary - GR is mostly dimeric upon ligand activation - GR’s final conformation might be a tetramer - GR-GR contacts depend on a complex, intertwined crosstalk within all structural domains: LBD, DBD, and likely the NTD - Is transrepression necessary to explain GR action?

Finally, Eva and Pablo’s team were able to crystallize GR’s LBD in a tetrameric form, giving us a unique opportunity to probe and test different oligomerization surfaces on GR. They even managed to capture GR tetramers in vitro with a GR DBD-LBD fragment! doi.org/10.1093/nar/...

By combing X-ray crystallography and live cell studies, Alba and Andrea were able to find new surfaces of GR-GR contacts, suggesting that several types of dimers can coexist in the cell

What was really missing, even though we already had live-cell experimental data, was the crystal structure of the tetramer. Here comes Eva and Pablo to the rescue!

Glucocorticoid receptor quaternary structure drives chromatin occupancy and transcriptional outcome

The idea that GR is a tetramer was received with high skepticism, to put it mildly, even though we demonstrated increased transcriptional activity for a constitutive tetrameric mutant receptor (GRtetra), www.genome.org/cgi/doi/10.1...

genome.org

An international, peer-reviewed genome sciences journal featuring outstanding original research that offers novel insights into the biology of all organisms

Back in 2016, we were able to quantify the oligomeric state of GR on a tandem array of DNA elements inside live cells, and we were shocked to find out that GR was actually a tetramer when bound to chromatin! doi.org/10.1073/pnas...

Insights on Glucocorticoid Receptor Activity Modulation through the Binding of Rigid Steroids

In 2010, we applied the N&B assay to quantify, for the first time, the oligomeric state of GR in live cells. Surprisingly, we find that the population of GR is mostly dimeric in the nucleus. Where are all the monomers? doi.org/10.1371/jour...

doi.org

Background The glucocorticoid receptor (GR) is a transcription factor that regulates gene expression in a ligand-dependent fashion. This modular protein is one of the major pharmacological targets due...

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This paper marks the culmination of a 15-year (and 7 papers) journey to challenge #Glucocorticoid-Receptor(GR) dogma. The classic paradigm of GR action states that monomeric GR and dimeric GR regulate a different set of genes