François Major

Université de Montréal | UdeM · Department of Computer Science and Operations Research

The majority of cancer deaths are caused by solid tumors, where the four most prevalent cancers (breast, lung, colorectal and prostate) account for more than 60% of all cases (1). Tumor cell heterogeneity driven by variable cancer microenvironments, such as hypoxia, is a key deter-minant of therapeutic outcome. We developed a novel culture protocol...

The majority of cancer deaths are caused by solid tumors, where the four most prevalent cancers (breast, lung, colorectal and prostate) account for more than 60% of all cases (1). Tumor cell het-erogeneity driven by variable cancer microenvironments, such as hypoxia, is a key determinant of therapeutic outcome. We developed a novel culture protocol...

Unlabelled: The DynaSig-ML ("Dynamical Signatures-Machine Learning") Python package allows the efficient, user-friendly exploration of 3D dynamics-function relationships in biomolecules, using datasets of experimental measures from large numbers of sequence variants. It does so by predicting 3D structural dynamics for every variant using the Elast...

The Elastic Network Contact Model (ENCoM) is a coarse-grained normal mode analysis (NMA) model unique in its all-atom sensitivity to the sequence of the studied macromolecule and thus to the effect of mutations. We adapted ENCoM to simulate the dynamics of ribonucleic acid (RNA) molecules, benchmarked its performance against other popular NMA model...

The DynaSig-ML (Dynamical Signatures - Machine Learning) Python package allows the efficient, user-friendly exploration of 3D dynamics-function relationships in biomolecules, using datasets of experimental measures from large numbers of sequence variants. The DynaSig-ML package is built around the Elastic Network Contact Model (ENCoM), the first an...

The DynaSig-ML (“Dynamical Signatures - Machine Learning”) Python package allows the efficient, user-friendly exploration of 3D dynamics-function relationships in biomolecules, using datasets of experimental measures from large numbers of sequence variants. The DynaSig-ML package is built around the Elastic Network Contact Model (ENCoM), the first...

The Elastic Network Contact Model (ENCoM) is a coarse-grained normal mode analysis (NMA) model unique in its all-atom sensitivity to the sequence of the studied macromolecule and thus to the effect of mutations. We adapted ENCoM to simulate the dynamics of ribonucleic acid (RNA) molecules, benchmarked its performance against other popular NMA model...

MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neoplastic cells by CD8 T cells. However, accurately predicting the MAP repertoire remains difficult, because only a fraction of the transcriptome generates MAPs. In this study, we investigated whether codon arrangement (usage and placement) regulates MAP...

MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neoplastic cells by CD8 T cells. However, accurately predicting the MAP repertoire remains difficult, because only a fraction of the transcriptome generates MAPs. In this study, we investigated whether codon arrangement (usage and placement) regulates MAP...

RNA-Puzzles is a collective endeavor dedicated to the advancement and improvement of RNA 3D structure prediction. With agreement from crystallographers, the RNA structures are predicted by various groups before the publication of the crystal structures. We now report the prediction of six RNA sequences: four structures of nucleolytic ribozymes and...

Cellular protein levels are finely tuned through microRNA-mediated gene regulation, triggered by RNA-induced silencing complexes (RISCs) that recognize, bind and silence mRNA targets. A recent study shows that, while mRNA target recognition is achieved with only about a third of the guide RNA sequence, formation of an efficient RISC conformation re...

Endothelial cells have multifaceted interactions with the immune system, both as initiators and targets of immune responses. In vivo, apoptotic endothelial cells release two types of extracellular vesicles upon caspase-3 activation: apoptotic bodies and exosome-like nanovesicles (ApoExos). Only ApoExos are immunogenic: their injection causes inflam...

MicroRNAs (miRNAs) are ribonucleic acids (RNAs) of ∼21 nucleotides that interfere with the translation of messenger RNAs (mRNAs) and play significant roles in development and diseases. In bilaterian animals, the specificity of miRNA targeting is determined by sequence complementarity involving the seed. However , the role of the remaining nucleotid...

MicroRNAs (miRNAs) are ribonucleic acids (RNAs) of ∼21 nucleotides that interfere with the translation of messenger RNAs (mRNAs) and play significant roles in development and diseases. In bilaterian animals, the specificity of miRNA targeting is determined by sequence complementarity involving the seed. However , the role of the remaining nucleotid...

Motivation The use of Normal Mode Analysis (NMA) methods to study both protein and nucleic acid dynamics is well established. However, the most widely used coarse-grained methods are based on backbone geometry alone and do not take into account the chemical nature of the residues. Elastic Network Contact Model (ENCoM) is a coarse-grained NMA method...

RNA structures are hierarchically organized. The secondary structure is articulated around sophisticated local three-dimensional (3D) motifs shaping the full 3D architecture of the molecule. Recent contributions have identified and organized recurrent local 3D motifs, but applications of this knowledge for predictive purposes is still in its infanc...

RNA structures are hierarchically organized. The secondary structure is articulated around sophisticated local three-dimensional (3D) motifs shaping the full 3D architecture of the molecule. Recent contributions have identified and organized recurrent local 3D motifs, but applications of this knowledge for predictive purposes is still in its infanc...

RNA-Puzzles is a collective experiment in blind 3D RNA structure prediction. We report here a third round of RNA-Puzzles. Five puzzles, 4, 8, 12, 13, 14, all structures of riboswitch aptamers and puzzle 7, a ribozyme structure, are included in this round of the experiment. The riboswitch structures include biological binding sites for small molecul...

MicroRNAs (miRNAs) are crucial gene expression regulators and first-order suspects in the development and progression of many diseases. Comparative analysis of cancer cell expression data highlights many deregulated miRNAs. Low expression of miR-125a was related to poor breast cancer prognosis. Interestingly, a single nucleotide polymorphism (SNP)...

We created an accelerated version of MC-Fold called MC-Flashfold that allows us to compute large numbers of competing secondary structures including noncanonical base pairs. We visualize the base pairs in these sets using high quality intuitive dot plots and arc plots. Our new tools allow us to explore RNA dynamics by visualizing the competing stru...

In eucaryotes, gene expression is regulated by microRNAs (miRNAs) which bind to messenger RNAs (mRNAs) and interfere with their translation into proteins, either by promoting their degradation or inducing their repression. We study the effect of miRNA interference on each gene using experimental methods, such as microarrays and RNA-seq at the mRNA...

We propose a complexity-theoretic approach to studying biological networks. We use a simple graph representation of biological networks capturing objects (molecules: DNA, RNA, proteins and chemicals) as nodes, and relations between them as directed and signed (promotional (+) or inhibitory (-)) edges. Based on this model, we formally define the pro...

This paper is a report of a second round of RNA-Puzzles, a collective and blind experiment in three-dimensional (3D) RNA structure prediction. Three puzzles, Puzzles 5, 6, and 10, represented sequences of three large RNA structures with limited or no homology with previously solved RNA molecules. A lariat-capping ribozyme, as well as riboswitches c...

ADARs (Adenosine deaminases that act on RNA) "edit" RNA by converting adenosines to inosines within double-stranded regions. The primary targets of ADARs are long duplexes present within noncoding regions of mRNAs, such as introns and 3' untranslated regions (UTRs). Because adenosine and inosine have different base-pairing properties, editing withi...

Anti-infection drugs target vital functions of infectious agents, including their ribosome and other essential non-coding RNAs. One of the reasons infectious agents become resistant to drugs is due to mutations that eliminate drug-binding affinity while maintaining vital elements. Identifying these elements is based on the determination of viable a...

Introduction Materials MC-Tools Troubleshooting References

Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian target of rapamycin (mTOR) is strongly implicated in ASDs by means of upstream signalling; however, downstream regulatory mechanisms are ill-defined. Here we show that knockout of the eukaryotic tran...

The prediction of RNA 3D structures from its sequence only is a milestone to RNA function analysis and prediction. In recent years, many methods addressed this challenge, ranging from cycle decomposition and fragment assembly to molecular dynamics simulations. However, their predictions remain fragile and limited to small RNAs. To expand the range...

We report the results of a first, collective, blind experiment in RNA three-dimensional (3D) structure prediction, encompassing three prediction puzzles. The goals are to assess the leading edge of RNA structure prediction techniques; compare existing methods and tools; and evaluate their relative strengths, weaknesses, and limitations in terms of...

Knowing the 3-D structure of an RNA is fundamental to understand its biological function. Nowadays X-ray crystallography and NMR spectroscopy are systematically applied to newly discovered RNAs. However, the application of these high-resolution techniques is not always possible, and thus scientists must turn to lower resolution alternatives. Here,...

We have previously shown that VegT mRNA plays a structural (translation-independent) role in the organization of the cytokeratin cytoskeleton in Xenopus oocytes. The depletion of VegT mRNA causes the fragmentation of the cytokeratin network in the vegetal cortex of Xenopus oocytes. This effect can be rescued by the injection of synthetic VegT RNA i...

The NMR solution structure is reported of a duplex, 5'GUGAAGCCCGU/3'UCACAGGAGGC, containing a 4 × 4 nucleotide internal loop from an R2 retrotransposon RNA. The loop contains three sheared purine-purine pairs and reveals a structural element found in other RNAs, which we refer to as the 3RRs motif. Optical melting measurements of the thermodynamics...

Tandem stretches of guanines can associate in hydrogen-bonded arrays to form G-quadruplexes, which are stabilized by K+ ions. Using computational methods, we searched for G-Quadruplex Sequence (GQS) patterns in the model plant species Arabidopsis thaliana. We found ∼1200 GQS with a G3 repeat sequence motif, most of which are located in the intergen...

Exploiting the experimental information from small-angle X-ray solution scattering (SAXS) in conjunction with structure prediction algorithms can be advantageous in the case of ribonucleic acids (RNA), where global restraints on the 3D fold are often lacking. Traditional usage of SAXS data often starts by attempting to reconstruct the molecular sha...

ABSTRACT : Increasingly sophisticated knowledge about RNA structure and function requires an inclusive knowledge representation that facilitates the integration of independently -generated information arising from such efforts as genome sequencing projects, microarray analyses, structure determination and RNA SELEX experiments. While RNAML, an XML-...

MicroRNAs (miRNAs) are naturally occurring small RNAs that regulate the expression of several genes. MiRNAs’ targeting rules are based on sequence complementarity between their mature products and targeted genes’ mRNAs. Based on our present understanding of those rules, we developed an algorithm to design artificial miRNAs to target simultaneously...

Adenosine-to-inosine (A-to-I) editing has been shown to be an important mechanism that increases protein diversity in the brain of organisms from human to fly. The family of ADAR enzymes converts some adenosines of RNA duplexes to inosines through hydrolytic deamination. The adenosine recognition mechanism is still largely unknown. Here, to investi...

To benchmark progress made in RNA three-dimensional modeling and assess newly developed techniques, reliable and meaningful comparison metrics and associated tools are necessary. Generally, the average root-mean-square deviations (RMSDs) are quoted. However, RMSD can be misleading since errors are spread over the whole molecule and do not account f...

Expression of the Bacillus subtilis trpEDCFBA operon is regulated by the interaction of tryptophan-activated TRAP with 11 (G/U)AG trinucleotide repeats that lie in the leader region of the nascent trp transcript. Bound TRAP prevents folding of an antiterminator structure and favors formation of an overlapping intrinsic terminator hairpin upstream o...

Substrate recognition by the VS ribozyme involves a magnesium-dependent loop/loop interaction between the SLI substrate and the SLV hairpin from the catalytic domain. Recent NMR studies of SLV demonstrated that magnesium ions stabilize a U-turn loop structure and trigger a conformational change for the extruded loop residue U700, suggesting a role...

The classical RNA secondary structure model considers A.U and G.C Watson-Crick as well as G.U wobble base pairs. Here we substitute it for a new one, in which sets of nucleotide cyclic motifs define RNA structures. This model allows us to unify all base pairing energetic contributions in an effective scoring function to tackle the problem of RNA fo...

The SCL and LMO oncogenes are frequently activated in childhood T cell acute leukemia (T-ALL). SCL is a bHLH transcription factor that forms heterodimers with other members, specifically HEB and E2A. SCL can either activate or repress transcription but its mechanism of action as an oncogene remains to be clarified. Ectopic expression of SCL and LMO...

Despite an increasing number of experimentally determined RNA structures, the gap between the number of structures and that of RNA families is still growing. To overcome this limitation, efficient and reliable RNA modeling methodologies must be developed. In order to reach this goal, here, we show how triloop sequence-structure relationships have b...

The formation of beta-sheet domains in proteins involves five energetically important factors: the formation of networks of hydrogen bonds and hydrophobic faces, and the residue propensities, or preferences, to be found at the edges of the beta-sheet, to adopt the extended conformation, and to make contact with other residues. These relative energy...

It is currently unknown how extensively the double-stranded RNA-binding protein Staufen (Stau)1 is utilized by mammalian cells to regulate gene expression. To date, Stau1 binding to the 3'-untranslated region (3'-UTR) of ADP ribosylation factor (ARF)1 mRNA has been shown to target ARF1 mRNA for Stau1-mediated mRNA decay (SMD). ARF1 SMD depends on t...

A new approach, graph-grammars, to encode RNA tertiary structure patterns is introduced and exemplified with the classical sarcin–ricin motif. The sarcin–ricin motif is found in the stem of the crucial ribosomal loop E (also referred to as the sarcin–ricin loop), which is sensitive to the α-sarcin and ricin toxins. Here, we generate a graph-grammar...

The E2F family of transcription factors is essential in the regulation of the cell cycle and apoptosis. While the activity of E2F1–3 is tightly controlled by the retinoblastoma family of proteins, the expression of these factors is also regulated at the level of transcription, post-translational modifications and protein stability. Recently, a new...

The aim of the RNA Ontology Consortium (ROC) is to create an integrated conceptual framework-an RNA Ontology (RO)-with a common, dynamic, controlled, and structured vocabulary to describe and characterize RNA sequences, secondary structures, three-dimensional structures, and dynamics pertaining to RNA function. The RO should produce tools for clear...

A minimum cycle basis of the tertiary structure of a large ribosomal subunit (LSU) X-ray crystal structure was analyzed. Most cycles are small, as they are composed of 3- to 5 nt, and repeated across the LSU tertiary structure. We used hierarchical clustering to quantify and classify the 4 nt cycles. One class is defined by the GNRA tetraloop motif...

The STT3 subunit of the oligosaccharyltransferase complex plays a critical role in the N-glycosylation process. From Arabidopsis thaliana to Homo sapiens, two functional STT3 isoforms have been identified, STT3-A and STT3-B. We report that the last transmembrane (TM) segment of STT3-B corresponds to a topogenic determinant that is sufficient for pr...

Systematic protein folding studies depend on protein three-dimensional structure annotation, the assignment of amino acid structural types from atomic coordinates. Significant stabilizing factors between adjacent beta-sheet peptide chains have recently been characterized and were not considered during the development of previously published annotat...

The SCL and LMO oncogenes are frequently activated in childhood T cell acute leukemia (T-ALL). SCL is a transcription factor of the basic helix-loop-helix (bHLH) family that forms heterodimers with other members of the family, specifically HEB and E2A. SCL can activate or repress transcription but the mechanism through which SCL functions as an onc...

In order to characterize regulatory genes that are expressed in ovule tissues after fertilization we have undertaken an EST sequencing project in Solanum chacoense, a self-incompatible wild potato species. Two cDNA libraries made from ovule tissues covering embryo development from zygote to late torpedo-stage were constructed and plated at high den...

Ribonucleic acid (RNA) tertiary structure prediction is an activity that consists of inferring complete sets of atomic coordinates of RNAs, in Euclidean space, on the basis of observation, knowledge or construct. The principal goal of prediction is to obtain precise RNA tertiary structures and, thus, to reduce the costs of the discovery process by...