Genetic research and Biotech science

Benoit Coulombe, PhD

Director, Department of Translational Proteomics, IRCM

Bell-Bombardier Research Chair, IRCM

Professor, Department of Biochemistry & Molecular Medicine, U of Montréal

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OVERALL GOAL

Our goal is to harness the power of proteomics to characterize the molecular defects that cause disease and develop biomarkers that can track the onset and the evolution of disease conditions, the response to treatment, and ultimately serve for the development of new diagnostics and therapeutics.

Our group adopts a resolutely innovative modus operandi, which contributes to shaking up our classic methods by creating a transdisciplinary and open ecosystem where totally distinct approaches collide to allow both the study of the atomic structure of proteins and their organization in complex networks, both the analysis of microscopic model systems and of patient cohorts, both the screening of small molecules and their development to create affordable drugs.

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To join our group as a graduate student or a postdoctoral fellow, please send a motivation letter and a complete CV by email directly to Benoit.Coulombe@ircm.qc.ca. Only candidates of interest will be contacted.

TOWARDS SINGLE-CELL PROTEOMICS

DEVELOPING SINGLE-CELL TECHNOLOGIES TO CRACK THE FULL COMPLEXITY OF THE HUMAN PROTEOME IN HEALTH, DISEASE, AND RESPONSE TO TREATMENT

Cells are the smallest structural and functional unit of living organisms. For more than a century, scientists have classified cells according to their structure, function, location, and, more recently, their molecular profile, but the characterization of cell types and states has remained limited. We do not comprehensively know our cells: how they are defined by their molecular products, how they vary across tissues, systems, and organs, and how they influence health and disease. This has hampered our ability to study key fundamental domains in biology, and to translate our knowledge to accelerate diagnosis and treatment.

However, transformative advances in experimental and computational methods now provide a unique opportunity to change this situation. Our ability to characterize the protein content of one cell at a time in tissues and organs, coupled with other omics and imaging technologies, is revolutionizing our knowledge. Our group is developing an innovative platform to perform high-throughput surveys of proteins, posttranslational modifications and interactions with single cell resolution.

DEVELOPING NEW GENERATION BIOMARKERS FOR THE MEDICINE OF TOMORROW

We also focus on the quantitative analysis of:

  • Protein levels using methods that either target specific proteins or achieve large-scale unbiased proteome screens

  • Posttranslational modifications

  • Protein-protein interactions and their inhibition by small molecules or peptides

The specific methods in place in our lab involve complex workflows mastered by our lab members, including

  • Protein Affinity Purification coupled to Mass Spectrometry (AP-MS)

  • Proximity-Dependent Protein Identification (BioID)

  • Tandem Mass Tag (TMT)-Based Discovery Proteomics

  • Protein Affinity Capture coupled to quantitative Mass Spectrometry (PAC-qMS)

  • Phage Display Peptide/Protein Library Screening (PhD)

We invite requests of collaboration not only from IRCM colleagues but also from researchers of other institutions. We usually accept to participate in projects we judge feasible and impactful, when a budget has been already secured by the collaborator. In some cases, we help with the preparation of grant applications. Our current collaborations target multiple diseases/biomarkers, including, but not limited to:

  • Leukodystrophies / RNA polymerase III

  • Amyotrophic Lateral Sclerosis / SOD1

  • Alzheimer's disease / Neuroligins

  • Cardiometabolic conditions / PCSK9, insulin

  • COVID-19 / SARS-CoV-2 S glycoprotein and replicase complex

Understanding the molecular defects that cause rare diseases is important to us. Mapping protein-protein interaction changes caused by rare disease-causing mutations is used to build the "Rare Disease Cell Map". This data is made available, often ahead of publication, at OpenforRare.com.

MOST RECENT PAPER

Figure 4:

The prefoldin-like module of the PAQosome. Schematic representation of prefoldin and prefoldin-like complexes subunit arrangement.

(A) Subunit arrangement of the canonical prefoldin complex. Archaeal prefoldin is used as a structural reference.

(B) Subunit composition of the canonical prefoldin complex (PFD) and prefoldin-like module (PFDL) of the PAQosome.

(C) Proposed subunit arrangement of the PFDL module.

(D) Simplified phylogenetic tree of the β-prefoldin family with local bootstrap indicated next to the nodes.

 

10 MOST CITED PAPERS FROM OUR LAB

1. Systematic Analysis of the Protein Interaction Network for the Human Transcription Machinery Reveals the Identity of the 7SK Capping Enzyme.

Jeronimo C, Forget D, Bouchard A, Li Q, Chua G, Poitras C, Thérien C, Bergeron D, Bourassa S, Greenblatt J, Chabot B, Poirier GG, Hughes TR, Blanchette M, Price DH, Coulombe B.

Mol Cell. 2007 Jul 20;27(2):262-74.  (404 citations)

Discovery of the 7SK methylphosphate capping enzyme and a series of chaperone-like proteins that associate with RNA polymerase to regulate its biogenesis, some being components of a chaperone complex later named “Particle for Arrangement of Quaternary structure” (PAQosome)

2. DNA Bending and Wrapping Around RNA Polymerase: A "Revolutionary" Model Describing Transcriptional Mechanisms.

Coulombe B, Burton ZF.

Microbiol Mol Biol Rev. 1999 Jun;63(2):457-78.  (153 citations)

3. A Newly Uncovered Group of Distantly Related Lysine Methyltransferases Preferentially Interact With Molecular Chaperones to Regulate Their Activity.

Cloutier P, Lavallée-Adam M, Faubert D, Blanchette M, Coulombe B.

PLoS Genet. 2013;9(1):e1003210.  (131 citations)

4. Wrapping of Promoter DNA Around the RNA Polymerase II Initiation Complex Induced by TFIIF.

Robert F, Douziech M, Forget D, Egly JM, Greenblatt J, Burton ZF, Coulombe B.

Mol Cell. 1998 Sep;2(3):341-51.  (126 citations)

5. Mechanism of Promoter Melting by the Xeroderma Pigmentosum Complementation Group B Helicase of Transcription Factor IIH Revealed by protein-DNA Photo-Cross-Linking.

Douziech M, Coin F, Chipoulet JM, Arai Y, Ohkuma Y, Egly JM, Coulombe B.

Mol Cell Biol. 2000 Nov;20(21):8168-77.  (89 citations)

6. High-resolution Mapping of the Protein Interaction Network for the Human Transcription Machinery and Affinity Purification of RNA Polymerase II-associated Complexes.

Cloutier P, Al-Khoury R, Lavallée-Adam M, Faubert D, Jiang H, Poitras C, Bouchard A, Forget D, Blanchette M, Coulombe B.

Methods. 2009 Aug;48(4):381-6.  (84 citations)

Composition of the R2TP/PFDL co-chaperone complex, later renamed “Particle for Arrangement of Quaternary structure” (PAQosome)

7. Structural Perspective on Mutations Affecting the Function of Multisubunit RNA Polymerases.
Trinh V, Langelier MF, Archambault J, Coulombe B.
Microbiol Mol Biol Rev. 2006 Mar;70(1):12-36.  (79 citations)

8. The Protein Interaction Network of the Human Transcription Machinery Reveals a Role for the Conserved GTPase RPAP4/GPN1 and Microtubule Assembly in Nuclear Import and Biogenesis of RNA Polymerase II.

Forget D, Lacombe AA, Cloutier P, Al-Khoury R, Bouchard A, Lavallée-Adam M, Faubert D, Jeronimo C, Blanchette M, Coulombe B.

Mol Cell Proteomics. 2010 Dec;9(12):2827-39.  (77 citations)

9. Recessive Mutations in POLR1C Cause a Leukodystrophy by Impairing Biogenesis of RNA Polymerase III.

Thiffault I, Wolf NI, Forget D, Guerrero K, Tran LT, Choquet K, Lavallée-Adam M, Poitras C, Brais B, Yoon G, Sztriha L, Webster RI, Timmann D, van de Warrenburg BP, Seeger J, Zimmermann A, Máté A, Goizet C, Fung E, van der Knaap MS, Fribourg S, Vanderver A, Simons C, Taft RJ, Yates JR 3rd, *Coulombe B, *Bernard G.

Nat Commun. 2015 Jul 7;6:7623. *Co-senior authors  (75 citations)

10. Photo-cross-linking of a Purified Preinitiation Complex Reveals Central Roles for the RNA Polymerase II Mobile Clamp and TFIIE in Initiation Mechanisms.

Forget D, Langelier MF, Thérien C, Trinh V, Coulombe B.

Mol Cell Biol. 2004 Feb;24(3):1122-31.  (73 citations)

 
 

TEAM

Dr. Benoit Coulombe
Dr. Benoit Coulombe
Director
Dr. Marie-Soleil Gauthier
Dr. Marie-Soleil Gauthier
Senior Associate Researcher
maxime_pinard_small.png
Dr. Maxime Pinard
Associate Researcher
esen_sokullu.png
Dr. Esen Sokullu
Postdoctoral Fellow
Samaneh_Dastpeyman.JPG
Dr. Samaneh Dastpeyman
Postdoctoral Fellow
Christian Poitras
Christian Poitras
Systems Analyst
Alexa Derksen
Alexa Derksen
Master Degree Student (Dr. G. Bernard)
Golden Marble
Vijaya Madhoo
Administrative Assistant
Diane Forget
Diane Forget
Honorary Lab Member

2020-06-26 :

Diane Forget prend sa retraite après 27 ans de service dévoué pour le laboratoire. Elle a eu

une contribution exceptionnelle pour nos publications, la formation de personnel, l'administration des fonds de recherche et la planification des espaces de laboratoire. Avec toute notre reconnaissance, merci et bonne continuation.

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