By using genetic and molecular approaches, we investigate the underlying processes leading to the development of complex cardiovascular disorders (CVDs), which are major contributors to morbidity and mortality worldwide. We have interests into how common noncoding gene variants control gene expression and drive network signalling pathways leading to vascular atheroma and heart valve fibrocalcification. We use prioritization of potential novel therapeutic targets and causal inference to track the molecular phenome of CVDs.
1. Integrative Mapping and Network Organization. Genome-wide association (GWA) studies and electronic health record databanks generate a wealth of genetic association data. However, for a vast majority of loci, causal gene variants and dysregulated genes remain unknown. We have developed several approaches to probe loci. We are interested into how functional annotation combined with Bayesian analyses and 3D genome mapping can decipher the genetic architecture of complex CVDs such as atheroma and heart valve disorders (HVDs). One important question we are probing is how haplotype-resolved data at loci may help identify causal gene variants and their targets. Complex trait disorders affect the expression of a large number of genes. Integration of data in network organization identify ‘hub genes’, which are often enriched in potential therapeutic targets. We are thus investigating how CVDs modify the landscape of gene networks and we look into how these approaches help prioritize ‘hub genes’ for follow-up functional studies.
2. Molecular quantitative traits and causal inference by using genetic association data. Multi ‘omics’ data, including several molecular quantitative traits (QTLs), offer opportunities for multidimensional mapping and causal inference. We are using several epigenetic and expression QTLs to further assess how gene variants impact the molecular phenome of CVDs. Integration of expression and protein QTLs with genetic association data allows causal inference by Mendelian Randomization (MR). By using MR, we are interested into how causal inference may help identify key causal genes in network prioritized pathways. Furthermore, by using Phenome-wide association analyses, we investigate how pleiotropy is acting on CVDs. For instance, how pleiotropy is manifested in inflammatory disorders and CVDs and affect longevity.
3. Functional Genomics and Molecular Pathway Characterization. One key central question we are probing is how common noncoding gene variants associated with complex trait disorders alter transcription factors (TFs), drivers of cell identity and fate, binding to DNA. Several algorithms are used in the lab to predict and prioritize causal variants based on their ability to modify TF binding sites (TFBS). Sequence information-based approaches as well as machine-learning algorithms are used to prioritize gene variants that may alter TF’s functions. Atomic-resolution data derived from published crystallographic studies are used to model potential molecular processes whereby a variant may affect protein-DNA interaction. We are interested into how these data may help predict experimental binding of TFs to DNA and their functional impacts. We explore several techniques such as DNA-binding, reporter assays and chromatin immunoprecipitation to functionally validate our models. At the cell level, we are probing how altered gene expression affects the function of vascular and valve cells. We exploit several cell and molecular assays to identify the interactome of dysregulated genes and its impact on cell function.
4. Control of gene expression. The transcriptional process is tightly regulated by several molecular complexes that affect the initiation, elongation and termination steps. One key question we are addressing is how gene transcription is regulated in complex disorders by epigenome regulators, gene variants and noncoding RNAs and how it interacts with genome looping. Both transcription and chromatin looping are intertwined in complex interactions, which may affect chromatin condensation. We explore how pause release of RNA Polymerase II is controlled by epigenome modifiers and noncoding RNAs at distant-acting enhancer and how it may impact on genome 3D organization. In addition, we investigate how novel protein complex may impact pause release and the production of nascent transcripts.
Congratulations to Mewen for his $500 prize for the second best oral presentation at the Research Day of the Department of Surgery, Faculty of Medicine, Laval University, in the "Research" category : Mendelian Randomization of the Circulating Proteome and Single Cell Sequencing Identify Molecular Phenome and Therapeutic Targets in Calcified Aortic Stenosis
Congratulations to Mewen for his paper in Scientific Reports: Connectome and regulatory hubs of CAGE highly active enhancers.
The hard work of our students Louis-Hippolyte Minvielle Moncla and Mewen Briend, as well as that of Dr. Patrick Mathieu has been rewarded today by the publication in Nature Reviews Cardiology : Calcific aortic valve disease: mechanisms, prevention and treatment.
Thanks to our colleague Dr. Yohan Bossé for his participation as well. Congratulations to all of you!
Welcome to Valentine Duclos from France who is joining Dr Mathieu's laboratory to undertake his PhD. Congratulations!
Congratulations to Hippolyte for his oral presentation at the IUCPQ 2022 Scientific Research Days (JSR 2022), which earned him first place and the $1000 FRQS prize !
Congratulations to Samuel for his paper in iScience: Genetic association and Mendelian randomization for hypothyroidism highlight immune molecular mechanisms.
Congratulations to Hippolyte for his paper in BMC Genomics: Mendelian randomization of circulating proteome identifies actionable targets in heart failure.
Welcome to our new summer interns Mame Sokhna Sylla, an undergraduate student in bioinformatics at Université Laval. A very good summer to you !
Congratulations to Arnaud for his paper in Human Genomics: Enhancer promoter interactome and Mendelian randomization identify network of druggable vascular genes in coronary artery disease.
Congratulations to Arnaud for his paper in PLoS Genetics: Genome-wide chromatin contacts of super-enhancer-associated lncRNA identify LINC01013 as a regulator of fibrosis in the aortic valve.
Welcome to Mewen Briand from France who is joining Dr Mathieu's laboratory to undertake his PhD. Congratulations!
Welcome to Louis-Hippolyte Minvielle Moncla from France who is joining Dr Mathieu's laboratory to undertake his PhD. Congratulations!