Publications
A gut meta-interactome map reveals modulation of human immunity by microbiome effectors (2023)
(2023). A gut meta-interactome map reveals modulation of human immunity by microbiome effectors. Manuscript under review (Nature). .
Project at Theories and Approaches of Genomic Complexity, Turing Centre for Living Systems, Aix-Marseille Université
Abstract: Article under review.
Short open reading frames-encoded peptides in human monocytes are involved in ubiquitous regulatory functions, metabolism and immunology responses (2022)
(2022). Short open reading frames-encoded peptides in human monocytes are involved in ubiquitous regulatory functions, metabolism and immunology responses. In preparation. .
Project at Theories and Approaches of Genomic Complexity, Turing Centre for Living Systems, Aix-Marseille Université
Abstract: Article in preparation. Short Open Reading Frames (sORFs) are ubiquitous genomic elements that have been overlooked for years. Some may encode functional peptides, so-called sORF-encoded peptides (sPEPs). Most of these lasts have failed to be annotated notably due to their short length (< 100 residues) and the use of alternative start codons (other than AUG). So far, the roles of only few sPEPs have been characterized and sPEPs whose functions have been determined are involved in a wide range of key biological processes (apoptosis, DNA reparation, transcriptional regulation, mTOR signaling, antigen presentation, cardiac activity regulation etc.). However, the functions of most sPEPs remains unknown. In this study, we propose a system approach to determine the functions of sPEPs in monocytes. We first predicted the interactions of sPEPs with canonical proteins (RefProts) and we analyzed the interfaces of interactions as well as the set of RefProts interacting with sPEPs. Based on the topology of the sPEP-canonical protein interaction network, we then predicted the function of the sPEPs. Our results suggest that the majority of sPEPs are involved in key biological functions, including regulatory functions and metabolism, immunology responses and cytoskeleton organization. Finally, we showed that sPEPs preferentially target RefProts involved in the same processes as their cognate RefProt. Our results suggest that sPEPs may be key regulator of both ubiquitous and specialized functions. They therefore should be of growing interest for the future proteome-wide analyses.
mimicINT: a workflow for microbe-host protein interaction inference (2022)
(2022). mimicINT: a workflow for microbe-host protein interaction inference. bioRxiv. doi: 10.1101/2022.11.04.515250.
Project at Theories and Approaches of Genomic Complexity, Turing Centre for Living Systems, Aix-Marseille Université
Abstract: The increasing incidence of emerging infectious diseases is posing serious global threats. Therefore, there is a clear need for developing computational methods that can assist and speed-up experimental research to better characterize the molecular mechanisms of microbial infections. In this context, we developed mimicINT, a freely available computational workflow for large-scale protein-protein interaction inference between microbe and human by detecting putative molecular mimicry elements that can mediate the interaction with host proteins: short linear motifs (SLiMs) and hostlike globular domains. mimicINT exploits these putative elements to infer the interaction with human proteins by using known templates of domain-domain and SLiM-domain interaction templates. mimicINT provides (i) robust Monte-Carlo simulations to assess the statistical significance of SLiM detection which suffers from false positive, and (ii) interaction specificity filter to account for differences between motif-binding domains of the same family. mimicINT is implemented in Python and R, and it is available at: https://github.com/TAGC-NetworkBiology/mimicINT.
In depth exploration of the alternative proteome of Drosophila melanogaster (2022)
(2022). In depth exploration of the alternative proteome of Drosophila melanogaster. Frontiers in Cell and Developmental Biology Cellular Biochemistry. eCollection 2022, doi: 10.3389/fcell.2022.901351.
Project at Theories and Approaches of Genomic Complexity, Turing Centre for Living Systems, Aix-Marseille Université
Abstract: Recent studies have shown that hundreds of small proteins were occulted when protein coding genes were annotated. These proteins, called alternative proteins, have failed to be annotated notably due to the short length of their open reading frame (less than 100 codons) or the enforced rule establishing that messenger RNAs (mRNAs) are monocystronic. Several alternative proteins were shown to be biologically active molecules and seem to be involved in a wide range of biological functions. However, genome wide exploration of the alternative proteome is still limited to a few species. In the present article we describe a deep peptidomics workflow which enabled the identification of 401 alternative proteins in Drosophila melanogaster. Subcellular localization, protein domains and short linear motifs were predicted for 235 of the alternative proteins identified and point towards specific functions of these small proteins. Several alternative proteins had approximated abundances higher than their canonical counterparts, suggesting that these alternative proteins are actually the main products of their corresponding genes. Finally, we observed fourteen alternative proteins with developmentally regulated expression patterns and ten induced upon heat shock treatment of embryos, demonstrating stage or stress specific production of alternative proteins.
MetamORF: A repository of unique short Open Reading Frames identified by both experimental and computational approaches for gene-level and meta-analysis (2021)
(2021). MetamORF: A repository of unique short Open Reading Frames identified by both experimental and computational approaches for gene-level and meta-analysis. Database. 2021:baab032, doi: 10.1093/database/baab032.
Project at Theories and Approaches of Genomic Complexity, Turing Centre for Living Systems, Aix-Marseille Université and Centre d'Immunologie de Marseille Luminy, Turing Centre for Living Systems, Aix-Marseille Université
Abstract: The development of high-throughput technologies revealed the existence of non-canonical short open reading frames (sORFs) on most eukaryotic RNAs. They are ubiquitous genetic elements conserved across species and suspected to be involved in numerous cellular processes. MetamORF (https://metamorf.hb.univ-amu.fr/) aims to provide a repository of unique sORFs identified in the human and mouse genomes with both experimental and computational approaches. By gathering publicly available sORF data, normalizing them and summarizing redundant information, we were able to identify a total of 1,162,675 unique sORFs. Despite the usual characterization of ORFs as short, upstream or downstream, there is currently no clear consensus regarding the definition of these categories. Thus, the data has been reprocessed using a normalized nomenclature. MetamORF enables new analyses at loci, gene, transcript and ORF levels, that should offer the possibility to address new questions regarding sORF functions in the future. The repository is available through an user-friendly web interface, allowing easy browsing, visualization, filtering over multiple criteria and export possibilities. sORFs could be searched starting from a gene, a transcript, an ORF ID, looking in a genome area or browsing the whole repository for a species. The database content has also been made available through track hubs at UCSC Genome Browser. Finally, we demonstrated an enrichment of genes harboring upstream open reading frames (uORFs) among genes expressed in response to reticular stress.
Proteostasis in dendritic cells is controlled by the PERK signaling axis independently of ATF4 (2020)
(2020). Proteostasis in dendritic cells is controlled by the PERK signaling axis independently of ATF4. Life Science Alliance. 21;4(2):e202000865 doi: 10.26508/lsa.202000865.
Project at Centre d'Immunologie de Marseille Luminy, Turing Centre for Living Systems, Aix-Marseille Université
Abstract: In stressed cells, phosphorylation of eukaryotic initiation factor 2α (eIF2α) controls transcriptome-wide changes in mRNA translation and gene expression known as the integrated stress response. We show here that DCs are characterized by high eIF2α phosphorylation, mostly caused by the activation of the ER kinase PERK (EIF2AK3). Despite high p-eIF2α levels, DCs display active protein synthesis and no signs of a chronic integrated stress response. This biochemical specificity prevents translation arrest and expression of the transcription factor ATF4 during ER-stress induction by the subtilase cytotoxin (SubAB). PERK inactivation, increases globally protein synthesis levels and regulates IFN-β expression, while impairing LPS-stimulated DC migration. Although the loss of PERK activity does not impact DC development, the cross talk existing between actin cytoskeleton dynamics; PERK and eIF2α phosphorylation is likely important to adapt DC homeostasis to the variations imposed by the immune contexts.
Transcoronary gradients of HDL-associated microRNAs in unstable coronary artery disease (2018)
(2018). Transcoronary gradients of HDL-associated microRNAs in unstable coronary artery. International Journal of Cardiology. 253:138144 doi:10.1016/j.card.2017.09.190.
Project at Lipid Research Group, School of Medical Science, University of New South Wales
Abstract: Aims: MicroRNAs (miRNAs) are transported on high-density lipoproteins (HDLs) and HDL-associated miRNAs are involved in intercellular communication. We explored HDL-associated miRNAs concentration gradients across the coronary circulation in stable and unstable coronary artery disease patients and whether changes in the transcoronary gradient were associated with changes in HDL composition and size.
Methods: Acute coronary syndrome (ACS, n = 17) patients, those with stable coronary artery disease (stable CAD, n = 19) and control subjects without CAD ( n = 6) were studied. HDLs were isolated from plasma obtained from the coronary sinus (CS), aortic root (arterial blood) and right atrium (venous blood). HDL-associated miRNAs (miR-16, miR-20a, miR-92a, miR-126, miR-222 and miR-223) were quantified by TaqMan miRNA assays. HDL particle sizes were determined by non-denaturing polyacrylamide gradient gel electrophoresis. HDL composition was measured immunoturbidometrically or enzymatically.
Results: A concentration gradient across the coronary circulation was observed for all the HDL-associated miRNAs. In ACS patients, there was a significant inverse transcoronary gradient for HDL-associated miR-16, miR-92a and miR-223 ( p < 0.05) compared to patients with stable CAD. Changes in HDL-miRNA transcoronary gradients were not associated with changes in HDL composition or size.
Conclusion: HDLs are depleted of miR-16, miR-92a and miR-223 during the transcoronary passage in patients with ACS compared to patients with stable CAD.
High-Density Lipoprotein-associated miR-223 is altered after diet-induced weight loss in overweight and obese males (2016)
(2016). High-Density Lipoprotein-associated miR-223 is altered after diet-induced weight loss in overweight and obese males. PLoS One. 11(3):e0151061 doi:10.1371/journal.pone.0151061.
Project at Lipid Research Group, School of Medical Science, University of New South Wales
Abstract: Background and Aims: microRNAs (miRNAs) are small, endogenous non-coding RNAs that regulate metabolic processes, including obesity. The levels of circulating miRNAs are affected by metabolic changes in obesity, as well as in diet-induced weight loss. Circulating miRNAs are transported by high-density lipoproteins (HDL) but the regulation of HDL-associated miRNAs after diet-induced weight loss has not been studied. We aim to determine if HDL-associated miR-16, miR-17, miR-126, miR-222 and miR-223 levels are altered by diet-induced weight loss in overweight and obese males.
Methods: HDL were isolated from 47 subjects following 12 weeks weight loss comparing a high protein diet (HP, 30% of energy) with a normal protein diet (NP, 20% of energy). HDL-associated miRNAs (miR-16, miR-17, miR-126, miR-222 and miR-223) at baseline and after 12 weeks of weight loss were quantified by TaqMan miRNA assays. HDL particle sizes were determined by non-denaturing polyacrylamide gradient gel electrophoresis. Serum concentrations of human HDL constituents were measured immunoturbidometrically or enzymatically.
Results: miR-16, miR-17, miR-126, miR-222 and miR-223 were present on HDL from overweight and obese subjects at baseline and after 12 weeks of the HP and NP weight loss diets. The HP diet induced a significant decrease in HDL-associated miR-223 levels (p = 0.015), which positively correlated with changes in body weight (r = 0.488, p = 0.032). Changes in miR-223 levels were not associated to changes in HDL composition or size.
Conclusion: HDL-associated miR-223 levels are significantly decreased after HP diet-induced weight loss in overweight and obese males. This is the first study reporting changes in HDL-associated miRNA levels with diet-induced weight loss.