Combining transcriptional and post-transcriptional regulation to predict somatic mutations altering the gene regulatory program in cancer cells

While most cancer studies focused on patient variations lying in protein-coding regions, the noncoding ~98% of the genome, containing cis-regulatory regions that control when and where genes are expressed, is largely unexplored. Transcription factors are key proteins binding to cis-regulatory regions to modulate the rate of gene transcription. Delineating the specific positions at which a TF binds DNA is of high importance in deciphering gene regulation. As cancer is a disease of disrupted cellular regulation, it is critical to analyze these regions to highlight patient somatic mutations altering the gene regulatory program of the cells. I will present our recent works on the evaluation of the combined effects of transcriptional and post-transcriptional dysregulation of gene expression. Our analyses culminated with the identification of mutations at TFBSs affecting the expression of key protein-coding and miRNA genes with a cascading dysregulating effect of the cells’ regulatory program. Our predictions were enriched for protein-coding and miRNA genes previously annotated as potential cancer drivers. Functional enrichment analyses highlighted the dysregulation of key pathways associated with carcinogenesis. These results confirm that our method predicts cis-regulatory mutations related to the dysregulation of key gene regulatory networks in cancer patients. This new strategy represents an original methodology to decipher how the gene regulatory program is disrupted in cancer cells by combining transcriptional and post-transcriptional regulation of gene expression

Chromosomal periodicity and positional networks of genes in Escherichia coli

Escherichia coli periodic gene distribution is identified for a periodic interval of 33 kb.Two positional networks of genes are discovered by studying gene periodic distribution: one is driven by metabolic genes and the other by genes involved in cellular processing and signaling.A functional core of Escherichia coli genes drives gene periodic distribution.A few chromosomal regions that preserve gene transcription profiles across environmental changes are identified.This single genome analysis approach can be taken as a footprint for a large-scale bacterial and archaeal periodic distribution analysis

A multi-view latent variable model reveals cellular heterogeneity in complex tissues for paired multimodal single-cell data

Motivation Single-cell multimodal assays allow us to simultaneously measure two different molecular features of the same cell, enabling new insights into cellular heterogeneity, cell development and diseases. However, most existing methods suffer from inaccurate dimensionality reduction for the joint-modality data, hindering their discovery of novel or rare cell subpopulations. Results Here, we present VIMCCA, a computational framework based on variational-assisted multi-view canonical correlation analysis to integrate paired multimodal single-cell data. Our statistical model uses a common latent variable to interpret the common source of variances in two different data modalities. Our approach jointly learns an inference model and two modality-specific non-linear models by leveraging variational inference and deep learning. We perform VIMCCA and compare it with 10 existing state-of-the-art algorithms on four paired multi-modal datasets sequenced by different protocols. Results demonstrate that VIMCCA facilitates integrating various types of joint-modality data, thus leading to more reliable and accurate downstream analysis. VIMCCA improves our ability to identify novel or rare cell subtypes compared to existing widely used methods. Besides, it can also facilitate inferring cell lineage based on joint-modality profiles

JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles.

International audienceJASPAR (http://jaspar.genereg.net) is an open-access database storing curated, non-redundant transcription factor (TF) binding profiles representing transcription factor binding preferences as position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor data package with the data of this release

JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles.

International audienceJASPAR (http://jaspar.genereg.net) is an open-access database storing curated, non-redundant transcription factor (TF) binding profiles representing transcription factor binding preferences as position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor data package with the data of this release

DNA copy number motifs are strong and independent predictors of survival in breast cancer.

Somatic copy number alterations are a frequent sign of genome instability in cancer. A precise characterization of the genome architecture would reveal underlying instability mechanisms and provide an instrument for outcome prediction and treatment guidance. Here we show that the local spatial behavior of copy number profiles conveys important information about this architecture. Six filters were defined to characterize regional traits in copy number profiles, and the resulting Copy Aberration Regional Mapping Analysis (CARMA) algorithm was applied to tumors in four breast cancer cohorts (n = 2919). The derived motifs represent a layer of information that complements established molecular classifications of breast cancer. A score reflecting presence or absence of motifs provided a highly significant independent prognostic predictor. Results were consistent between cohorts. The nonsite-specific occurrence of the detected patterns suggests that CARMA captures underlying replication and repair defects and could have a future potential in treatment stratification

An integrated expression atlas of miRNAs and their promoters in human and mouse

MicroRNAs (miRNAs) are short non-coding RNAs with key roles in cellular regulation. As part of the fifth edition of the Functional Annotation of Mammalian Genome (FANTOM5) project, we created an integrated expression atlas of miRNAs and their promoters by deep-sequencing 492 short RNA (sRNA) libraries, with matching Cap Analysis Gene Expression (CAGE) data, from 396 human and 47 mouse RNA samples. Promoters were identified for 1,357 human and 804 mouse miRNAs and showed strong sequence conservation between species. We also found that primary and mature miRNA expression levels were correlated, allowing us to use the primary miRNA measurements as a proxy for mature miRNA levels in a total of 1,829 human and 1,029 mouse CAGE libraries. We thus provide a broad atlas of miRNA expression and promoters in primary mammalian cells, establishing a foundation for detailed analysis of miRNA expression patterns and transcriptional control regions

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution

Etude de faisabilité d'introduction d'un guide touristique axé citoyen dans le contexte genevois

Nous sommes une association de bénévoles qui a décidé d’étudier la faisabilité d’introduction d’un guide « touristique » destiné aux concitoyens dans le contexte genevois dès 2009. L’objectif de cet ouvrage est de palier à une difficulté d’accès à l’information concernant tous les lieux et activités que nous offre la Ville de Genève. En effet, nous désirons faire apparaître les rubriques suivantes : Infos pratiques, Loisirs, Culture, Restaurant, Sorties nocturnes, Petit plaisir, Utile afin d’offrir au lecteur une vaste palette de choix d’activités. Pour ce faire, nous avons formulé des hypothèses découlant de questions que nous nous posions et qui, une fois les réponses trouvées, nous ont permis d’affirmer l’existence du problème précité. Pour arriver à ce constat, nous avons dû travailler en deux étapes qui représentent les grandes parties de ce dossier. Tout d’abord, nous avons effectué un travail de recherches caractérisé par une analyse interne de l’association, une analyse externe du marché genevois et une étude de terrain par sondages pour vérifier nos impressions et définir plus précisément les attentes de la population. Cette première partie nous a permis de définir nos axes stratégiques sur lesquels nous allions tabler pour pénétrer le marché et concrétiser notre produit. Ensuite, nous sommes passé à une partie plus pratique qui a eu pour objet de mettre en place tous les éléments concrets de création du guide, du choix du support jusqu’aux engagements publicitaires de la première édition en passant par la réalisation physique d’une maquette appropriée à la personnalité du contexte genevois. Finalement, nous avons pu en conclure que notre désir de mettre sur pied cet ouvrage était réalisable avec une projection de 2800 pièces dès la première année accompagnée d’un site Internet pour offrir une plus grande capacité de consultation. Ce chiffre peut paraître petit pour une ville comme Genève qui compte plus de 450'000 habitants, mais une fois rapporté aux nombres de ménages, cela représente tout de même un ouvrage pour une trentaine de foyer correspondant ainsi à la production espérée