Transcribing RNA polymerase

Translational Proteomics Laboratory, IRCM

Director: Dr. Benoit Coulombe

Bell-Bombardier Research Chair, IRCM

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

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A single-cell proteogenomics platform for the development of cell-based medicine

Our laboratory is setting in place a high-throughput single-cell proteogenomics platform that harnesses the phage display technology to profile massively both the proteome and the transcriptome of individual cells, using a suite of methods we named scPHAGE-seq and scPHAGE-ms. We aim to track changes in gene expression programs with unrivaled precision along the trajectory of cells from normal to disease conditions. This information will serve in the development of a novelmedical paradigm, cell-based medicine, for early disease detection and treatment before tissue damage and symptoms are present.

 

We are part of the 37TrillionCells Initiative

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a research partner of the EU LifeTime initiative
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Single-cell genomics, particularly transcriptome profiling using scRNA-seq, has greatly advanced our understanding of gene expression programs and improved the quality of the molecular signatures for predicting disease conditions. Indeed, classical methods measure RNA and proteins in populations of cells, generating results that are the average of what is found in many different cells and masking the effects that occur at the individual cell level that are often crucial. Conversely, single-cell (sc) analyses capture these differences.

Because proteins are the functional actors of cells, combining protein profiles with RNA profiles allows to dissect gene expression networks with unrivaled precision. This being said, the development of single-cell mass spectrometry-based proteomics represents a main challenge, as mass spectrometry is currently not sensitive, nor robust enough to profile the proteome of individual cells with sufficient depth. scPHAGE-seqand scPHAGE-ms, by exploiting large libraries of recombinant antibodies displayed on phages, helps to tackle this issue.

Bacteriophage Viruses

LEUKODYSTROPHIES

In collaboration with the laboratories of Drs. Geneviève Bernard (MUHC, McGill) and Bernard Brais (MNI/Neuro, McGill), we have shown that some leukodystrophy-causing mutations producing amino acid changes in RNA polymerase III subunits impair normal assembly and biogenesis of this 17-subunit enzyme. We are now seeking for chemical compounds that can revert these assembly defects. We are also developing a single-cell multiomic approach to help studying the molecular mechanisms leading to leukodytrophies.

COVID-19 / SARS-COV-2

We have developed a phage display platform to identify peptides and recombinant antibodies that bind the SARS-COV-2 Spike glycoprotein with high affinity and impair virus entry in target cells. A number of peptides have been selected to assess biological and biochemical properties.

DIABETES AND HYPERCHOLESTEROLEMIA

By studying the cholesterolemia-regulatory factor PCSK9, we have defined new roles for this protein in patients, particularly phosphorylated forms that can be used as biomarkers in various diseases. We now use single-cell multiomic approaches to characterize gene expression programs in cardiometabolic diseases (diabetes, dyslipidemia).

ALZHEIMER'S DISEASE

We measure the level of key biomarkers in the blood of patients to assess their role in the evolution of Alzheimer's disease. We have also launched a project aimed at using single-cell proteogenomics to characterize gene expression programs in cells of animal models for this disease.

Our group adopts a resolutely innovative modus operandi, which contributes to shaking up our classical 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.

To join the Coulombe lab 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.

RECENT PUBLICATIONS (2018-21)

Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

Deepthi Sudarshan, Nikita Avvakumov, Marie-Eve Lalonde, Nader Alerasool, Karine Jacquet, Amel Mameri, Justine Rousseau, Jean-Philippe Lambert, Eric Paquet, Samarth Thonta Setty, Jeremy Loehr, Anne-Claude Gingras, Benoit Coulombe, Mikko Taipale, Yannick Doyon, Jacques Cote

https://doi.org/10.1101/2021.03.26.436670

Biallelic pathogenic variants in LSM7impair assembly of LSM complexes, impairs neurodevelopment in zebrafish and may be associated with an ultra rare neurodevelopmental and neurodegenerative disorder

Derksen A, Shih HY, Forget D, Darbelli L, Tran LT, Poitras C, Guerrero K, Tharun S, Alkuraya FS, Kurdi WI, Nguyen CTE, Laberge AM, Si Y, Gauthier MS, Bonkowsky J*, Coulombe B*, Bernard G*. (*Co-senior authors)

HGG Adv. In Press.

POLR3-related leukodystrophy: How do mutations affecting RNA polymerase III subunits cause hypomyelination?

Coulombe B, Derksen A, La Piana R, Brais B, Gauthier MS, Bernard G.

Fac Rev. 2021 Feb 5;10:12.

De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy

Djordjevic D, Pinard M, Gauthier MS, Smith-Hicks C, Hoffman TL, Wolf NI, Oegema R, van Binsbergen E, Baskin B, Bernard G, Fribourg S, Coulombe B, Yoon G.

Am J Hum Genet. 2021 Jan 7;108(1):186-193.

Upstream ORF-Encoded ASDURF Is a Novel Prefoldin-like Subunit of the PAQosome

Cloutier P, Poitras C, Faubert D, Bouchard A, Blanchette M, Gauthier MS, Coulombe B.

J Proteome Res. 2020 Jan 3;19(1):18-27.

Ser-Phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (Family With Sequence Similarity 20, Member C) Kinase Enhances Its Ability to Degrade the LDLR (Low-Density Lipoprotein Receptor)

Ben Djoudi Ouadda A, Gauthier MS, Susan-Resiga D, Girard E, Essalmani R, Black M, Marcinkiewicz J, Forget D, Hamelin J, Evagelidis A, Ly K, Day R, Galarneau L, Corbin F, Coulombe B, Çaku A, Tagliabracci VS, Seidah NG.

Arterioscler Thromb Vasc Biol. 2019 Oct;39(10):1996-2013.

The leukodystrophy mutation Polr3b R103H causes homozygote mouse embryonic lethality and impairs RNA polymerase III biogenesis

Choquet K, Pinard M, Yang S, Moir RD, Poitras C, Dicaire MJ, Sgarioto N, Larivière R, Kleinman CL, Willis IM, Gauthier MS, Coulombe B, Brais B.

Mol Brain. 2019 Jun 20;12(1):59.

Leukodystrophy-associated POLR3A mutations down-regulate the RNA polymerase III transcript and important regulatory RNA BC200

Choquet K, Forget D, Meloche E, Dicaire MJ, Bernard G, Vanderver A, Schiffmann R, Fabian MR, Teichmann M, Coulombe B, Brais B, Kleinman CL.

J Biol Chem. 2019 May 3;294(18):7445-7459.

Role of the PAQosome in Regulating Arrangement of Protein Quaternary Structure in Health and Disease

Gauthier MS, Cloutier P, Coulombe B.

Adv Exp Med Biol. 2018;1106:25-36.

How do our cells build their protein interactome?

Coulombe B, Cloutier P, Gauthier MS.

Nat Commun. 2018 Jul 27;9(1):2955.

Posttranslational modification of proprotein convertase subtilisin/kexin type 9 is differentially regulated in response to distinct cardiometabolic treatments as revealed by targeted proteomics

Gauthier MS, Awan Z, Bouchard A, Champagne J, Tessier S, Faubert D, Chabot K, Garneau PY, Rabasa-Lhoret R, Seidah NG, Ridker PM, Genest J, Coulombe B.

J Clin Lipidol. 2018 Jul-Aug;12(4):1027-1038.

Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy

Mendes MI, Gutierrez Salazar M, Guerrero K, Thiffault I, Salomons GS, Gauquelin L, Tran LT, Forget D, Gauthier MS, Waisfisz Q, Smith DEC, Simons C, van der Knaap MS, Marquardt I, Lemes A, Mierzewska H, Weschke B, Koehler W, Coulombe B, Wolf NI, Bernard G.

Am J Hum Genet. 2018 Apr 5;102(4):676-684.

The PAQosome, an R2TP-Based Chaperone for Quaternary Structure Formation

Houry WA, Bertrand E, Coulombe B.

Trends Biochem Sci. 2018 Jan;43(1):4-9.

 
 

TEAM

Dr. Benoit Coulombe
Dr. Benoit Coulombe
Director
Dr. Marie-Soleil Gauthier
Dr. Marie-Soleil Gauthier
Senior Associate Researcher
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Dr. Maxime Pinard
Associate Researcher
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Dr. Esen Sokullu
Postdoctoral Fellow
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Asmae Moursli
PhD student
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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