Regulation of gene expression

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The overall goal of our research is to better understand how nutrient availability regulates gene expression to control cell fate decisions.

The regulation of gene expression plays a fundamental role in the ability of cells to adapt to environmental fluctuations. Signaling pathways integrate external cues to drive specific gene expression programs that dictate, for example, whether a cell will proliferate or stay quiescent. Gene regulation can occur at many distinct steps. For example, it has been well-characterized that growth factors and nutrients promote proliferation through the TOR kinase, which regulates protein synthesis. Another critical point of control is transcription, which is regulated by many transcription factors and co-factors, including the SAGA complex. Finally, these factors all function within larger macro-molecular complexes which assembly depends on specific chaperones. Our lab tackles two essential questions to better understand how cells allow both coordination and versatility in gene expression.

1. Mechanism of coordinated gene expression regulation in response to nutrient availability:

Each regulatory step has been studied in great details in many organisms and it is largely accepted that these processes must be synchronized, rather than operating independently. However, little is known about the molecular mechanisms underlying such coordination.

2. Characterization of chaperone-mediated assembly of regulatory complexes:

These processes involve several large, multi-protein complexes with multiple regulatory activities. Few studies have investigated how these complexes are assembled, whether their assembly can be regulated to control their activities, and which specific chaperones are involved.

Experimental systems, approaches, and specific aims:

To address these issues, we combine classical molecular, cell biology, genetics, and biochemistry assays with cutting-edge genomic, proteomic, and structural biology approaches, using both the fission yeast Schizosaccharomyces pombe and human cancer cell lines, as experimental systems.

In the presence of nutrients, particularly of a good nitrogen source, S. pombe cells grow and proliferate. In contrast, in starvation conditions, they exit the cell cycle and differentiate into a quiescent state. In this yeast, we decipher the mechanisms by which nutrient-sensing kinases control transcription and chromatin regulators. In parallel, we explore the roles of dedicated chaperones in the coordinated assembly of these factors into their active macro-molecular complexes.

In parallel, we investigate whether similar processes contribute to control the balance between proliferation and quiescence of cancer cells. Indeed, given the high conservation of these factors, what we learn in yeast is likely to be relevant to other, ‘slower-growing’ eukaryotes. This issue is important because some cancer cells could exit quiescence, resume proliferation and cause tumor relapse. Forcing these cells to stay dormant could be an effective way of stopping tumor recurrence following conventional therapies.

 

Interested in our work? Contact dom [at] helmlinger [dot] com

Follow us on Twitter, LinkedIn, ResearchGate, and ORCID (0000-0003-1501-0423).

Contact our team

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Dominique Helmlinger

Members of the team

  • Dylane DETILLEUX
    (PhD Student) +33 (0)4 34 35 95 49
  • Alberto ELIAS VILLALOBOS
    (Post-Doc) +33 (0)4 34 35 95 49
  • Celine FAUX
    (Research Assistant) +33 (0)4 34 35 95 51
  • Dominique HELMLINGER Group Leader
    ( CRCN) +33 (0)4 34 35 95 51
  • Berengere PRADET-BALADE
    (CRCN) (+33) 04 34 35 95 48
  • Peggy RAYNAUD
    (Staff Scientist) +33 (0)4 34 35 95 49
  • Damien TOULLEC
    (PhD Student) +33 (0)4 34 35 95 49
  • Aida YAZBAK
    (Trainee) +33 (0)4 34 35 9
    • 2017

      TORC1 and TORC2 converge to regulate the SAGA co-activator in response to nutrient availability.

      Laboucarié T, Detilleux D, Rodriguez-Mias RA, Faux C, Romeo Y, Franz-Wachtel M, Krug K, Maček B, Villén J, Petersen J,[...]

      EMBO Rep. pii: e201744942. Pubmed

    • 2017

      Sharing the SAGA.

      Helmlinger D, Tora L.

      Trends Biochem Sci. S0968-0004(17)30168-8. Pubmed

    • 2015

      The Hos2 Histone Deacetylase Controls Ustilago maydis Virulence through Direct Regulation of Mating-Type Genes.

      Elías-Villalobos A, Fernández-Álvarez A, Moreno-Sánchez I, Helmlinger D, Ibeas JI.

      PLoS Pathog. 11:e1005134. Pubmed

    • 2014

      Drosophila Spag is the homolog of RNA polymerase II-associated protein 3 (RPAP3) and recruits the heat shock proteins 70 and 90 (Hsp70 and Hsp90) during the assembly of cellular machineries.

      Benbahouche Nel H, Iliopoulos I, Török I, Marhold J, Henri J, Kajava AV, Farkaš R, Kempf T, Schnölzer M, Meyer[...]

      J Biol Chem. 289:6236-47. Pubmed

    • 2012

      HSP90 and the R2TP co-chaperone complex: building multi-protein machineries essential for cell growth and gene expression.

      Boulon S, Bertrand E, Pradet-Balade B.

      RNA Biol. 9(2):148-54. Pubmed

    • 2012

      New insights into the SAGA complex from studies of the Tra1 subunit in budding and fission yeast.

      Helmlinger D.

      Transcription. 3(1):13-8. Pubmed

    • 2011

      CRM1 controls the composition of nucleoplasmic pre-snoRNA complexes to licence them for nucleolar transport.

      Pradet-Balade B, Girard C, Boulon S, Paul C, Azzag K, Bordonné R, Bertrand E, Verheggen C.

      EMBO J. 30(11):2205-18. Pubmed

    • 2011

      Tra1 has specific regulatory roles, rather than global functions, within the SAGA co-activator complex.

      Helmlinger D, Marguerat S, Villén J, Swaney DL, Gygi SP, Bähler J, Winston F.

      EMBO J. 30(14):2843-52. Pubmed

    • 2010

      HSP90 and its R2TP/Prefoldin-like cochaperone are involved in the cytoplasmic assembly of RNA polymerase II.

      Boulon S, Pradet-Balade B, Verheggen C, Molle D, Boireau S, Georgieva M, Azzag K, Robert MC, Ahmad Y, Neel H,[...]

      Mol Cell. 39(6):912-924. Pubmed

    • 2008

      The S. pombe SAGA complex controls the switch from proliferation to sexual differentiation through the opposing roles of its subunits Gcn5 and Spt8.

      Helmlinger D, Marguerat S, Villén J, Gygi SP, Bähler J, Winston F.

      Genes Dev. 22(22):3184-95. Pubmed

    NEWS:

    10/2017 – Thomas Laboucarié’s work on the regulation of SAGA by the TOR kinase pathways is published in EMBO Reports. Congrats!

    09/2017 – Our review with László Tora about sharing the SAGA is out in Trends in Biochemical Sciences.

    02/2017 – Diana Bachrouche joins the lab from the Lebanese University for her Master thesis – welcome!

    10/2016 – Welcome to our new PhD student, Damien Toullec who joins with an EpiGenMed fellowship!

    06/2016 – Funding! INCa grant awarded together with E. Bertrand and M. Hahne teams @IGMM.

    01/2016 – Damien Toullec joins from the University of Rennes for his Master internship – welcome!

    04/2015 – Thomas Laboucarié PhD defense – congrats to the first PhD graduate of the lab and best wishes in the vineyards!

    09/2015 – Paper! Alberto’s study of the Hos2 HDAC in Ustilago is published.

    08/2015 – Fundings! ANR JCJC “CoCoNut” and PRC “SAGA2” grants awarded.

    07/2015 – Dom gets the HDR diploma from the University of Montpellier.

    07/2015 – Céline Faux joins the lab as a lab manager – welcome!

    03/2015 – Kerstin Wagner joins the lab from the University of Vienna for her Master thesis – welcome!

    12/2014 – Dylane Detilleux gets a PhD fellowship from the Ligue Nationale Contrer le Cancer and joins the lab!

    10/2014 – Bérengère Pradet-Balade (CR1, CNRS) gets the HDR diploma from the University of Montpellier and joins the lab – welcome!

    12/2013 – Fundings! ARC “Projets 2013”; ATIP grant extended; Marie Curie Career Integration Grants.

    11/2013 – Dylane Detilleux joins from the University of Montpellier for her Master internship – welcome!

    10/2013 – William Johnson joins the lab from the University of Manchester for his Erasmus undergrad exchange program – welcome!

    07/2013 – Alberto Elias-Villalobos from Sevilla University gets a postdoc fellowship and joins the lab – welcome!

    06/2013 – ‘Emergences’ grant from the Cancéropôle Grand Sud-Ouest.

    10/2012 – Thomas Laboucarié gets an EpiGenMed PhD fellowship and joins the lab – welcome!

    07/2012 – Yves Romeo gets a tenured lecturer position at the University of Toulouse – congrats!

    12/2011 – Yves Romeo from McGill University gets a postdoc fellowship and joins the lab – welcome!

    01/08/2011: Opening Day and first member to join – Gwenda Lledo! Yes we can!