Biology subjects

Lefebvre, F.

Publications and source records attributed to Lefebvre, F..

6 recordsLinked to original sources

bioRxiv2025

PARPAL: PARalog Protein Redistribution using Abundance and Localization in Yeast Database

Whole-genome duplication (WGD) events are common across various organisms however the retention and evolution of WGD paralogs is not fully understood. Quantitative measure of protein redistribution in response to the deletion of their WGD paralog provides insight into sources of gene retention. Here, we describe PARPAL (PARalog Protein Retribution using Abundance and Localization in Yeast), a web database that houses results of high-content screening and deep learning neural network analysis of the redistribution of 164 proteins reflecting how their subcellular localization and protein abundance change in response to their paralog deletion. We interrogated a total of 82 paralog pairs in two genetic backgrounds for a total of [~]3,500 micrographs of [~]460,000 cells. PARPAL also links to other studies on trigenic interactions, protein-protein interactions and protein abundance. PARPAL is available at https://parpal.c3g-app.sd4h.ca and is a valuable resource for the yeast community interested in understanding the retention and evolution of paralogs and can help researchers to investigate protein dynamics of paralogs in other organisms.

systems biology↗

bioRxiv2023

WEGS: a cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome

0Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a novel, cost-effective method, which we call "Whole Exome Genome Sequencing" (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7-2.0 times cheaper than standard WES (no-plexing), 1.8-2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus.

genomics↗

bioRxiv2021

EPAC1 Inhibition Protects the Heart from Doxorubicin-Induced Toxicity

Anthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the Exchange Protein directly Activated by cAMP (EPAC) in Dox-induced cardiotoxicity and the potential cardioprotective effects of EPAC inhibition. We show that Dox induces DNA damage and cardiomyocyte cell death with apoptotic features. Dox also led to an increase in both cAMP concentration and EPAC1 activity. The pharmacological inhibition of EPAC1 (with CE3F4) but not EPAC2 alleviated the whole Dox-induced pattern of alterations. When administered in vivo, Dox-treated WT mice developed a dilated cardiomyopathy which was totally prevented in EPAC1 KO mice. Moreover, EPAC1 inhibition potentiated Dox-induced cell death in several human cancer cell lines. Thus, EPAC1 inhibition appears as a potential therapeutic strategy to limit Dox-induced cardiomyopathy without interfering with its antitumoral activity.

pathology↗

bioRxiv2021

Ribosomes in RNA granules are stalled on mRNA sequences that are consensus sites for FMRP association.

Local translation in neurons is mediated in part by the reactivation of stalled polysomes. Stalled polysomes may be enriched within the pellet of sucrose gradients used to separate polysomes from monosomes. We find that this fraction, isolated from P5 rat brains of both sexes, is enriched in proteins implicated in stalled polysome function, such as the fragile X mental retardation protein (FMRP) and Up-frameshift mutation 1 homolog (UPF1). Cryo-EM analysis of ribosomes in this fraction indicates they are stalled, mainly in the hybrid state. Ribosome profiling of this fraction showed an abundance of footprint reads derived from mRNAs of cytoskeletal proteins implicated in neuronal development and an enrichment of footprint reads on RNA binding proteins. Compared to those usually found in ribosome profiling studies, the footprint reads were more extended on their 3end and were found in reproducible peaks in the mRNAs. These peaks were enriched in motifs previously associated with mRNAs cross-linked to FMRP in vivo, independently linking the ribosomes in the sedimented pellet to the ribosomes associated with FMRP in the cell. The data supports a model in which specific sequences in mRNAs act to stall translation elongation in neurons.

neuroscience↗

bioRxiv2019

Absence of subcerebral projection neurons delays disease onset and extends survival in a mouse model of ALS

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of adulthood that affects voluntary motricity and rapidly leads to full paralysis and death. ALS arises from the combined degeneration of motoneurons in the spinal cord and brain stem, responsible for muscle denervation, and corticospinal projection neurons (CSN), responsible for emergence of the upper motor neuron syndrome. Recent studies carried on ALS patients suggest that the disease may initiate in the motor cortex and spread to its projection targets. However, this "corticofugal hypothesis" of ALS has not yet been specifically challenged. Here, we provide a direct test of this hypothesis by genetically removing subcerebral projection neurons (SubCerPN), including CSN, in Sod1G86R mice, a mouse model of ALS. Ablation of the transcription factor Fezf2, leading to the complete absence of all SubCerPN, delays disease onset, reduces weight loss and motor impairment, and increases survival without modifying disease duration. Importantly absence of SubCerPN and CSN also limits pre-symptomatic hyperreflexia. Together, our results demonstrate that major corticofugal tracts are critical to ALS onset, and that SubCerPN and CSN in particular may carry detrimental signals to their downstream targets. In its whole, this study provides first experimental arguments in favour of the corticofugal hypothesis of ALS.

neuroscience↗

bioRxiv2018

GenPipes: an open-source framework for distributed and scalable genomic analyses

With the decreasing cost of sequencing and the rapid developments in genomics technologies and protocols, the need for validated bioinformatics software that enables efficient large-scale data processing is growing. Here we present GenPipes, a flexible Python-based framework that facilitates the development and deployment of multi-step workflows optimized for High Performance Computing clusters and the cloud. GenPipes already implements 12 validated and scalable pipelines for various genomics applications, including RNA-Seq, ChIP-Seq, DNA-Seq, Methyl-Seq, Hi-C, capture Hi-C, metagenomics and PacBio long read assembly. The software is available under a GPLv3 open source license and is continuously updated to follow recent advances in genomics and bioinformatics. The framework has been already configured on several servers and a docker image is also available to facilitate additional installations. In summary, GenPipes offers genomic researchers a simple method to analyze different types of data, customizable to their needs and resources, as well as the flexibility to create their own workflows.

bioinformatics↗