Human phospho‐signaling networks of SARS‐CoV‐2 infection are rewired by population genetic variants

SARS‐CoV‐2 infection hijacks signaling pathways and induces protein–protein interactions between human and viral proteins. Human genetic variation may impact SARS‐CoV‐2 infection and COVID‐19 pathology; however, the genetic variation in these signaling networks remains uncharacterized. Here, we studied human missense single nucleotide variants (SNVs) altering phosphorylation sites modulated by SARS‐CoV‐2 infection, using machine learning to identify amino acid substitutions altering kinase‐bound sequence motifs. We found 2,033 infrequent phosphorylation‐associated SNVs (pSNVs) that are enriched in sequence motif alterations, potentially reflecting the evolution of signaling networks regulating host defenses. Proteins with pSNVs are involved in viral life cycle and host responses, including RNA splicing, interferon response (TRIM28), and glucose homeostasis (TBC1D4) with potential associations with COVID‐19 comorbidities. pSNVs disrupt CDK and MAPK substrate motifs and replace these with motifs of Tank Binding Kinase 1 (TBK1) involved in innate immune responses, indicating consistent rewiring of signaling networks. Several pSNVs associate with severe COVID‐19 and hospitalization (STARD13, ARFGEF2). Our analysis highlights potential genetic factors contributing to inter‐individual variation of SARS‐CoV‐2 infection and COVID‐19 and suggests leads for mechanistic and translational studies

Comprehensive transcriptome analysis of mouse embryonic stem cell adipogenesis unravels new processes of adipocyte development

International audienceBACKGROUND: The current epidemic of obesity has caused a surge of interest in the study of adipose tissue formation. While major progress has been made in defining the molecular networks that control adipocyte terminal differentiation, the early steps of adipocyte development and the embryonic origin of this lineage remain largely unknown. RESULTS: Here we performed genome-wide analysis of gene expression during adipogenesis of mouse embryonic stem cells (ESCs). We then pursued comprehensive bioinformatic analyses, including de novo functional annotation and curation of the generated data within the context of biological pathways, to uncover novel biological functions associated with the early steps of adipocyte development. By combining in-depth gene regulation studies and in silico analysis of transcription factor binding site enrichment, we also provide insights into the transcriptional networks that might govern these early steps. CONCLUSIONS: This study supports several biological findings: firstly, adipocyte development in mouse ESCs is coupled to blood vessel morphogenesis and neural development, just as it is during mouse development. Secondly, the early steps of adipocyte formation involve major changes in signaling and transcriptional networks. A large proportion of the transcription factors that we uncovered in mouse ESCs are also expressed in the mouse embryonic mesenchyme and in adipose tissues, demonstrating the power of our approach to probe for genes associated with early developmental processes on a genome-wide scale. Finally, we reveal a plethora of novel candidate genes for adipocyte development and present a unique resource that can be further explored in functional assays

g:Profiler—a web server for functional interpretation of gene lists (2011 update)

Functional interpretation of candidate gene lists is an essential task in modern biomedical research. Here, we present the 2011 update of g:Profiler (http://biit.cs.ut.ee/gprofiler/), a popular collection of web tools for functional analysis. g:GOSt and g:Cocoa combine comprehensive methods for interpreting gene lists, ordered lists and list collections in the context of biomedical ontologies, pathways, transcription factor and microRNA regulatory motifs and protein–protein interactions. Additional tools, namely the biomolecule ID mapping service (g:Convert), gene expression similarity searcher (g:Sorter) and gene homology searcher (g:Orth) provide numerous ways for further analysis and interpretation. In this update, we have implemented several features of interest to the community: (i) functional analysis of single nucleotide polymorphisms and other DNA polymorphisms is supported by chromosomal queries; (ii) network analysis identifies enriched protein–protein interaction modules in gene lists; (iii) functional analysis covers human disease genes; and (iv) improved statistics and filtering provide more concise results. g:Profiler is a regularly updated resource that is available for a wide range of species, including mammals, plants, fungi and insects

Comprehensive reanalysis of transcription factor knockout expression data in Saccharomyces cerevisiae reveals many new targets

Transcription factor (TF) perturbation experiments give valuable insights into gene regulation. Genome-scale evidence from microarray measurements may be used to identify regulatory interactions between TFs and targets. Recently, Hu and colleagues published a comprehensive study covering 269 TF knockout mutants for the yeast Saccharomyces cerevisiae. However, the information that can be extracted from this valuable dataset is limited by the method employed to process the microarray data. Here, we present a reanalysis of the original data using improved statistical techniques freely available from the BioConductor project. We identify over 100 000 differentially expressed genes—nine times the total reported by Hu et al. We validate the biological significance of these genes by assessing their functions, the occurrence of upstream TF-binding sites, and the prevalence of protein–protein interactions. The reanalysed dataset outperforms the original across all measures, indicating that we have uncovered a vastly expanded list of relevant targets. In summary, this work presents a high-quality reanalysis that maximizes the information contained in the Hu et al. compendium. The dataset is available from ArrayExpress (accession: E-MTAB-109) and it will be invaluable to any scientist interested in the yeast transcriptional regulatory system

g:Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments

g:Profiler (http://biit.cs.ut.ee/gprofiler/) is a public web server for characterising and manipulating gene lists resulting from mining high-throughput genomic data. g:Profiler has a simple, user-friendly web interface with powerful visualisation for capturing Gene Ontology (GO), pathway, or transcription factor binding site enrichments down to individual gene levels. Besides standard multiple testing corrections, a new improved method for estimating the true effect of multiple testing over complex structures like GO has been introduced. Interpreting ranked gene lists is supported from the same interface with very efficient algorithms. Such ordered lists may arise when studying the most significantly affected genes from high-throughput data or genes co-expressed with the query gene. Other important aspects of practical data analysis are supported by modules tightly integrated with g:Profiler. These are: g:Convert for converting between different database identifiers; g:Orth for finding orthologous genes from other species; and g:Sorter for searching a large body of public gene expression data for co-expression. g:Profiler supports 31 different species, and underlying data is updated regularly from sources like the Ensembl database. Bioinformatics communities wishing to integrate with g:Profiler can use alternative simple textual outputs

Publisher Correction: Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma.

The original version of this Article omitted Suzana A. Kahn, Siddhartha S. Mitra & Samuel H. Cheshier as jointly supervising authors. This has now been corrected in both the PDF and HTML versions of the Article

Integrative pathway enrichment analysis of multivariate omics data

Multi-omics datasets represent distinct aspects of the central dogma of molecular biology. Such high-dimensional molecular profiles pose challenges to data interpretation and hypothesis generation. ActivePathways is an integrative method that discovers significantly enriched pathways across multiple datasets using statistical data fusion, rationalizes contributing evidence and highlights associated genes. As part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumor types, we integrated genes with coding and non-coding mutations and revealed frequently mutated pathways and additional cancer genes with infrequent mutations. We also analyzed prognostic molecular pathways by integrating genomic and transcriptomic features of 1780 breast cancers and highlighted associations with immune response and anti-apoptotic signaling. Integration of ChIP-seq and RNA-seq data for master regulators of the Hippo pathway across normal human tissues identified processes of tissue regeneration and stem cell regulation. ActivePathways is a versatile method that improves systems-level understanding of cellular organization in health and disease through integration of multiple molecular datasets and pathway annotations