Path-seq identifies an essential mycolate remodeling program for mycobacterial host adaptation
The success of Mycobacterium tuberculosis (MTB) stems from its ability to remain hidden from the immune system within macrophages. Here, we report a new technology (Path-seq) to sequence miniscule amounts of MTB transcripts within up to million-fold excess host RNA. Using Path-seq and regulatory network analyses, we have discovered a novel transcriptional program for in vivo mycobacterial cell wall remodeling when the pathogen infects alveolar macrophages in mice. We have discovered that MadR transcriptionally modulates two mycolic acid desaturases desA1/desA2 to initially promote cell wall remodeling upon in vit...
Source: Molecular Systems Biology - March 3, 2019 Category: Molecular Biology Authors: Peterson, E. J., Bailo, R., Rothchild, A. C., Arrieta-Ortiz, M. L., Kaur, A., Pan, M., Mai, D., Abidi, A. A., Cooper, C., Aderem, A., Bhatt, A., Baliga, N. S. Tags: Genome-Scale & Integrative Biology, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) affects 25% of the population and can progress to cirrhosis with limited treatment options. As the liver secretes most of the blood plasma proteins, liver disease may affect the plasma proteome. Plasma proteome profiling of 48 patients with and without cirrhosis or NAFLD revealed six statistically significantly changing proteins (ALDOB, APOM, LGALS3BP, PIGR, VTN, and AFM), two of which are already linked to liver disease. Polymeric immunoglobulin receptor (PIGR) was significantly elevated in both cohorts by 170% in NAFLD and 298% in cirrhosis and was further validated in mouse mode...
Source: Molecular Systems Biology - March 1, 2019 Category: Molecular Biology Authors: Niu, L., Geyer, P. E., Wewer Albrechtsen, N. J., Gluud, L. L., Santos, A., Doll, S., Treit, P. V., Holst, J. J., Knop, F. K., Vilsboll, T., Junker, A., Sachs, S., Stemmer, K., Müller, T. D., Tschöp, M. H., Hofmann, S. M., Mann, M. Tags: Genome-Scale & Integrative Biology, Molecular Biology of Disease, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Unraveling the hidden universe of small proteins in bacterial genomes
Identification of small open reading frames (smORFs) encoding small proteins (≤ 100 amino acids; SEPs) is a challenge in the fields of genome annotation and protein discovery. Here, by combining a novel bioinformatics tool (RanSEPs) with "-omics" approaches, we were able to describe 109 bacterial small ORFomes. Predictions were first validated by performing an exhaustive search of SEPs present in Mycoplasma pneumoniae proteome via mass spectrometry, which illustrated the limitations of shotgun approaches. Then, RanSEPs predictions were validated and compared with other tools using proteomic datasets from different ...
Source: Molecular Systems Biology - February 22, 2019 Category: Molecular Biology Authors: Miravet-Verde, S., Ferrar, T., Espadas-Garcia, G., Mazzolini, R., Gharrab, A., Sabido, E., Serrano, L., Lluch-Senar, M. Tags: Microbiology, Virology & Host Pathogen Interaction, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
De novo gene signature identification from single-cell RNA-seq with hierarchical Poisson factorization
We present single-cell hierarchical Poisson factorization (scHPF), a Bayesian factorization method that adapts hierarchical Poisson factorization (Gopalan et al, 2015, Proceedings of the 31st Conference on Uncertainty in Artificial Intelligence, 326) for de novo discovery of both continuous and discrete expression patterns from scRNA-seq. scHPF does not require prior normalization and captures statistical properties of single-cell data better than other methods in benchmark datasets. Applied to scRNA-seq of the core and margin of a high-grade glioma, scHPF uncovers marked differences in the abundance of glioma subpopu...
Source: Molecular Systems Biology - February 22, 2019 Category: Molecular Biology Authors: Levitin, H. M., Yuan, J., Cheng, Y. L., Ruiz, F. J., Bush, E. C., Bruce, J. N., Canoll, P., Iavarone, A., Lasorella, A., Blei, D. M., Sims, P. A. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology Methods Source Type: research
Unsupervised identification of disease states from high-dimensional physiological and histopathological profiles
The liver and kidney in mammals play central roles in protecting the organism from xenobiotics and are at high risk of xenobiotic-induced injury. Xenobiotic-induced tissue injury has been extensively studied from both classical histopathological and biochemical perspectives. Here, we introduce a machine-learning approach to analyze toxicological response. Unsupervised characterization of physiological and histological changes in a large toxicogenomic dataset revealed nine discrete toxin-induced disease states, some of which correspond to known pathology, but others were novel. Analysis of dynamics revealed transitions betw...
Source: Molecular Systems Biology - February 19, 2019 Category: Molecular Biology Authors: Shimada, K., Mitchison, T. J. Tags: Computational Biology, Molecular Biology of Disease, Systems Medicine Articles Source Type: research
Quantification and discovery of sequence determinants of protein-per-mRNA amount in 29 human tissues
Despite their importance in determining protein abundance, a comprehensive catalogue of sequence features controlling protein-to-mRNA (PTR) ratios and a quantification of their effects are still lacking. Here, we quantified PTR ratios for 11,575 proteins across 29 human tissues using matched transcriptomes and proteomes. We estimated by regression the contribution of known sequence determinants of protein synthesis and degradation in addition to 45 mRNA and 3 protein sequence motifs that we found by association testing. While PTR ratios span more than 2 orders of magnitude, our integrative model predicts PTR ratios at a me...
Source: Molecular Systems Biology - February 18, 2019 Category: Molecular Biology Authors: Eraslan, B., Wang, D., Gusic, M., Prokisch, H., Hallström, B. M., Uhlen, M., Asplund, A., Ponten, F., Wieland, T., Hopf, T., Hahne, H., Kuster, B., Gagneur, J. Tags: Genome-Scale & Integrative Biology, Methods & Resources, RNA Biology Articles Source Type: research
A deep proteome and transcriptome abundance atlas of 29 healthy human tissues
Genome-, transcriptome- and proteome-wide measurements provide insights into how biological systems are regulated. However, fundamental aspects relating to which human proteins exist, where they are expressed and in which quantities are not fully understood. Therefore, we generated a quantitative proteome and transcriptome abundance atlas of 29 paired healthy human tissues from the Human Protein Atlas project representing human genes by 18,072 transcripts and 13,640 proteins including 37 without prior protein-level evidence. The analysis revealed that hundreds of proteins, particularly in testis, could not be detected even...
Source: Molecular Systems Biology - February 18, 2019 Category: Molecular Biology Authors: Wang, D., Eraslan, B., Wieland, T., Hallström, B., Hopf, T., Zolg, D. P., Zecha, J., Asplund, A., Li, L.-h., Meng, C., Frejno, M., Schmidt, T., Schnatbaum, K., Wilhelm, M., Ponten, F., Uhlen, M., Gagneur, J., Hahne, H., Kuster, B. Tags: Genome-Scale & Integrative Biology, Methods & Resources Articles Source Type: research
Temporal order and precision of complex stress responses in individual bacteria
Sudden stress often triggers diverse, temporally structured gene expression responses in microbes, but it is largely unknown how variable in time such responses are and if genes respond in the same temporal order in every single cell. Here, we quantified timing variability of individual promoters responding to sublethal antibiotic stress using fluorescent reporters, microfluidics, and time-lapse microscopy. We identified lower and upper bounds that put definite constraints on timing variability, which varies strongly among promoters and conditions. Timing variability can be interpreted using results from statistical kineti...
Source: Molecular Systems Biology - February 14, 2019 Category: Molecular Biology Authors: Mitosch, K., Rieckh, G., Bollenbach, T. Tags: Microbiology, Virology & Host Pathogen Interaction, Quantitative Biology & Dynamical Systems, Transcription Articles Source Type: research
Widespread inter-individual gene expression variability in Arabidopsis thaliana
A fundamental question in biology is how gene expression is regulated to give rise to a phenotype. However, transcriptional variability is rarely considered although it could influence the relationship between genotype and phenotype. It is known in unicellular organisms that gene expression is often noisy rather than uniform, and this has been proposed to be beneficial when environmental conditions are unpredictable. However, little is known about inter-individual transcriptional variability in multicellular organisms. Using transcriptomic approaches, we analysed gene expression variability between individual Arabidopsis t...
Source: Molecular Systems Biology - January 24, 2019 Category: Molecular Biology Authors: Cortijo, S., Aydin, Z., Ahnert, S., Locke, J. C. Tags: Genome-Scale & Integrative Biology, Plant Biology, Transcription Articles Source Type: research
Complex-centric proteome profiling by SEC-SWATH-MS
Proteins are major effectors and regulators of biological processes that can elicit multiple functions depending on their interaction with other proteins. The organization of proteins into macromolecular complexes and their quantitative distribution across these complexes is, therefore, of great biological and clinical significance. In this paper, we describe an integrated experimental and computational technique to quantify hundreds of protein complexes in a single operation. The method consists of size exclusion chromatography (SEC) to fractionate native protein complexes, SWATH/DIA mass spectrometry to precisely quantif...
Source: Molecular Systems Biology - January 14, 2019 Category: Molecular Biology Authors: Heusel, M., Bludau, I., Rosenberger, G., Hafen, R., Frank, M., Banaei-Esfahani, A., van Drogen, A., Collins, B. C., Gstaiger, M., Aebersold, R. Tags: Methods & Resources, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
High-resolution mapping of cancer cell networks using co-functional interactions
Powerful new technologies for perturbing genetic elements have recently expanded the study of genetic interactions in model systems ranging from yeast to human cell lines. However, technical artifacts can confound signal across genetic screens and limit the immense potential of parallel screening approaches. To address this problem, we devised a novel PCA-based method for correcting genome-wide screening data, bolstering the sensitivity and specificity of detection for genetic interactions. Applying this strategy to a set of 436 whole genome CRISPR screens, we report more than 1.5 million pairs of correlated "co-functional...
Source: Molecular Systems Biology - December 20, 2018 Category: Molecular Biology Authors: Boyle, E. A., Pritchard, J. K., Greenleaf, W. J. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Computational Biology, Network Biology Articles Source Type: research
From prioritisation to understanding: mechanistic predictions of variant effects
The widespread application of sequencing technologies, used for example to obtain data from healthy individuals or patient cohorts, has led to the identification of numerous mutations, the effect of which remains largely unclear. Therefore, developing approaches allowing accurate in-silico prediction of mutation effects is becoming increasingly important. In their recent study, Beltrao and colleagues (Wagih et al, 2018) describe an integrative approach for determining the effects of mutations from the perspective of protein structure, conservation and transcription factor binding. This allows for predicting the mechan...
Source: Molecular Systems Biology - December 20, 2018 Category: Molecular Biology Authors: Slodkowicz, G., Babu, M. M. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Computational Biology, Methods & Resources News [amp ] Views Source Type: research
A resource of variant effect predictions of single nucleotide variants in model organisms
The effect of single nucleotide variants (SNVs) in coding and noncoding regions is of great interest in genetics. Although many computational methods aim to elucidate the effects of SNVs on cellular mechanisms, it is not straightforward to comprehensively cover different molecular effects. To address this, we compiled and benchmarked sequence and structure-based variant effect predictors and we computed the impact of nearly all possible amino acid and nucleotide variants in the reference genomes of Homo sapiens, Saccharomyces cerevisiae and Escherichia coli. Studied mechanisms include protein stability, interaction interfa...
Source: Molecular Systems Biology - December 20, 2018 Category: Molecular Biology Authors: Wagih, O., Galardini, M., Busby, B. P., Memon, D., Typas, A., Beltrao, P. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Computational Biology, Methods & Resources Articles Source Type: research
Data citation: what, when, why?
EMBO Press has implemented a structured Data Availability Section as well as formal data citations in research articles at all its journals. This serves to improve access to research data and provide a mechanism for credit attribution to data producers. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - December 17, 2018 Category: Molecular Biology Authors: Lemberger, T. Tags: Editorial Source Type: research
Dynamic control of endogenous metabolism with combinatorial logic circuits
Controlling gene expression during a bioprocess enables real-time metabolic control, coordinated cellular responses, and staging order-of-operations. Achieving this with small molecule inducers is impractical at scale and dynamic circuits are difficult to design. Here, we show that the same set of sensors can be integrated by different combinatorial logic circuits to vary when genes are turned on and off during growth. Three Escherichia coli sensors that respond to the consumption of feedstock (glucose), dissolved oxygen, and by-product accumulation (acetate) are constructed and optimized. By integrating these sensors, log...
Source: Molecular Systems Biology - November 27, 2018 Category: Molecular Biology Authors: Moser, F., Espah Borujeni, A., Ghodasara, A. N., Cameron, E., Park, Y., Voigt, C. A. Tags: Methods & Resources, Synthetic Biology & Biotechnology Articles Source Type: research
