Ready, Set...Poised!: Polycomb target genes are bound by poised RNA polymerase II throughout differentiation
In embryonic stem cells (ESCs), silent genes with major developmental functions display a unique epigenetic state in which strong and broad binding by Polycomb repressive complexes (PRCs) is accompanied by the presence of poised RNA polymerase II (RNAPII) and activating histone marks (e.g. H3K4me3) (Azuara et al, 2006; Bernstein et al, 2006; Stock et al, 2007; Brookes et al, 2012). It has been suggested that the plasticity and broad differentiation potential of pluripotent cells might rely, at least partly, on this unique epigenetic state (Bernstein et al, 2006; Stock et al, 2007). In their re...
Source: Molecular Systems Biology - October 23, 2017 Category: Molecular Biology Authors: Rada-Iglesias, A. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Transcription News [amp ] Views Source Type: research
Lysine acetylome profiling uncovers novel histone deacetylase substrate proteins in Arabidopsis
In this study, we determined the proteome-wide signatures of the RPD3/HDA1 class of histone deacetylases in Arabidopsis. Relative quantification of the changes in the lysine acetylation levels was determined on a proteome-wide scale after treatment of Arabidopsis leaves with deacetylase inhibitors apicidin and trichostatin A. We identified 91 new acetylated candidate proteins other than histones, which are potential substrates of the RPD3/HDA1-like histone deacetylases in Arabidopsis, of which at least 30 of these proteins function in nucleic acid binding. Furthermore, our analysis revealed that histone deacetylase 14 (HDA...
Source: Molecular Systems Biology - October 23, 2017 Category: Molecular Biology Authors: Hartl, M., Füssl, M., Boersema, P. J., Jost, J.-O., Kramer, K., Bakirbas, A., Sindlinger, J., Plöchinger, M., Leister, D., Uhrig, G., Moorhead, G. B., Cox, J., Salvucci, M. E., Schwarzer, D., Mann, M., Finkemeier, I. Tags: Methods & Resources, Plant Biology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Drug detoxification dynamics explain the postantibiotic effect
The postantibiotic effect (PAE) refers to the temporary suppression of bacterial growth following transient antibiotic treatment. This effect has been observed for decades for a wide variety of antibiotics and microbial species. However, despite empirical observations, a mechanistic understanding of this phenomenon is lacking. Using a combination of modeling and quantitative experiments, we show that the PAE can be explained by the temporal dynamics of drug detoxification in individual cells after an antibiotic is removed from the extracellular environment. These dynamics are dictated by both the export of the antibiotic a...
Source: Molecular Systems Biology - October 23, 2017 Category: Molecular Biology Authors: Srimani, J. K., Huang, S., Lopatkin, A. J., You, L. Tags: Microbiology, Virology & Host Pathogen Interaction, Quantitative Biology & Dynamical Systems Articles Source Type: research
In situ genotyping of a pooled strain library after characterizing complex phenotypes
In this work, we present a proof-of-principle experiment that extends advanced live cell microscopy to the scale of pool-generated strain libraries. We achieve this by identifying the genotypes for individual cells in situ after a detailed characterization of the phenotype. The principle is demonstrated by single-molecule fluorescence time-lapse imaging of Escherichia coli strains harboring barcoded plasmids that express a sgRNA which suppresses different genes in the E. coli genome through dCas9 interference. In general, the method solves the problem of characterizing complex dynamic phenotypes for diverse genet...
Source: Molecular Systems Biology - October 17, 2017 Category: Molecular Biology Authors: Lawson, M. J., Camsund, D., Larsson, J., Baltekin, O., Fange, D., Elf, J. Tags: Methods & Resources, Quantitative Biology & Dynamical Systems Source Type: research
RNA polymerase II primes Polycomb-repressed developmental genes throughout terminal neuronal differentiation
Polycomb repression in mouse embryonic stem cells (ESCs) is tightly associated with promoter co-occupancy of RNA polymerase II (RNAPII) which is thought to prime genes for activation during early development. However, it is unknown whether RNAPII poising is a general feature of Polycomb repression, or is lost during differentiation. Here, we map the genome-wide occupancy of RNAPII and Polycomb from pluripotent ESCs to non-dividing functional dopaminergic neurons. We find that poised RNAPII complexes are ubiquitously present at Polycomb-repressed genes at all stages of neuronal differentiation. We observe both loss and acqu...
Source: Molecular Systems Biology - October 16, 2017 Category: Molecular Biology Authors: Ferrai, C., Torlai Triglia, E., Risner-Janiczek, J. R., Rito, T., Rackham, O. J., de Santiago, I., Kukalev, A., Nicodemi, M., Akalin, A., Li, M., Ungless, M. A., Pombo, A. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Transcription Articles Source Type: research
CRISPR/Cas9 screening using unique molecular identifiers
Loss-of-function screening by CRISPR/Cas9 gene knockout with pooled, lentiviral guide libraries is a widely applicable method for systematic identification of genes contributing to diverse cellular phenotypes. Here, Random Sequence Labels (RSLs) are incorporated into the guide library, which act as unique molecular identifiers (UMIs) to allow massively parallel lineage tracing and lineage dropout screening. RSLs greatly improve the reproducibility of results by increasing both the precision and the accuracy of screens. They reduce the number of cells needed to reach a set statistical power, or allow a more robust screen us...
Source: Molecular Systems Biology - October 9, 2017 Category: Molecular Biology Authors: Schmierer, B., Botla, S. K., Zhang, J., Turunen, M., Kivioja, T., Taipale, J. Tags: Genome-Scale & Integrative Biology, Methods & Resources Source Type: research
De novo MYC addiction as an adaptive response of cancer cells to CDK4/6 inhibition
Cyclin-dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through metabolic and transcriptomic analyses, we show that the inhibition of CDK4/6 leads to a metabolic reprogramming associated with gene networks orchestrated by the MYC transcription factor. Upon inhibition of CDK4/6, an accumulation of MYC protein ensues which explains an increased glutamine metabolism, activation of the mTOR pathway and blunting of HIF-1α-mediated responses to hypoxia. These MYC-driven adaptations to CDK4/6 inhibition render cancer cells highly sensitive to...
Source: Molecular Systems Biology - October 4, 2017 Category: Molecular Biology Authors: Tarrado-Castellarnau, M., de Atauri, P., Tarrago-Celada, J., Perarnau, J., Yuneva, M., Thomson, T. M., Cascante, M. Tags: Cancer, Metabolism, Signal Transduction Articles Source Type: research
A theory that predicts behaviors of disordered cytoskeletal networks
Morphogenesis in animal tissues is largely driven by actomyosin networks, through tensions generated by an active contractile process. Although the network components and their properties are known, and networks can be reconstituted in vitro, the requirements for contractility are still poorly understood. Here, we describe a theory that predicts whether an isotropic network will contract, expand, or conserve its dimensions. This analytical theory correctly predicts the behavior of simulated networks, consisting of filaments with varying combinations of connectors, and reveals conditions under which networks of rigid f...
Source: Molecular Systems Biology - September 27, 2017 Category: Molecular Biology Authors: Belmonte, J. M., Leptin, M., Nedelec, F. Tags: Cell Adhesion, Polarity & Cytoskeleton, Quantitative Biology & Dynamical Systems Articles Source Type: research
It's easier to get along with the quiet neighbours
Why are neighbouring genes co-expressed at the RNA level? While it is tempting to think that this is to enable coordination of functionally related proteins, analysis of human proteomics data by Rappsilber and colleagues (Kustatscher et al, 2017) suggests this is the exception not the rule. Rather it might either be just something that happens or, in some instances, an epiphenomenon of coordination of expression to enable reduced gene expression noise. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - September 26, 2017 Category: Molecular Biology Authors: Hurst, L. D. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology News [amp ] Views Source Type: research
Revisiting biomarker discovery by plasma proteomics
Clinical analysis of blood is the most widespread diagnostic procedure in medicine, and blood biomarkers are used to categorize patients and to support treatment decisions. However, existing biomarkers are far from comprehensive and often lack specificity and new ones are being developed at a very slow rate. As described in this review, mass spectrometry (MS)-based proteomics has become a powerful technology in biological research and it is now poised to allow the characterization of the plasma proteome in great depth. Previous "triangular strategies" aimed at discovering single biomarker candidates in small cohorts, follo...
Source: Molecular Systems Biology - September 26, 2017 Category: Molecular Biology Authors: Geyer, P. E., Holdt, L. M., Teupser, D., Mann, M. Tags: Molecular Biology of Disease, Post-translational Modifications, Proteolysis & Proteomics, Systems Medicine Reviews Source Type: research
An immediate-late gene expression module decodes ERK signal duration
(Source: Molecular Systems Biology)
Source: Molecular Systems Biology - September 25, 2017 Category: Molecular Biology Authors: Uhlitz, F., Sieber, A., Wyler, E., Fritsche-Guenther, R., Meisig, J., Landthaler, M., Klinger, B., Blüthgen, N. Tags: Corrigendum Source Type: research
A proteomic atlas of insulin signalling reveals tissue-specific mechanisms of longevity assurance
Lowered activity of the insulin/IGF signalling (IIS) network can ameliorate the effects of ageing in laboratory animals and, possibly, humans. Although transcriptome remodelling in long-lived IIS mutants has been extensively documented, the causal mechanisms contributing to extended lifespan, particularly in specific tissues, remain unclear. We have characterized the proteomes of four key insulin-sensitive tissues in a long-lived Drosophila IIS mutant and control, and detected 44% of the predicted proteome (6,085 proteins). Expression of ribosome-associated proteins in the fat body was reduced in the mutant, with a corresp...
Source: Molecular Systems Biology - September 15, 2017 Category: Molecular Biology Authors: Tain, L. S., Sehlke, R., Jain, C., Chokkalingam, M., Nagaraj, N., Essers, P., Rassner, M., Grönke, S., Froelich, J., Dieterich, C., Mann, M., Alic, N., Beyer, A., Partridge, L. Tags: Ageing, Post-translational Modifications, Proteolysis & Proteomics, Signal Transduction Articles Source Type: research
Pervasive coexpression of spatially proximal genes is buffered at the protein level
We present evidence that non-functional mRNA coexpression in human cells arises from stochastic chromatin fluctuations and direct regulatory interference between spatially close genes. Protein-level buffering likely reflects a lack of coordination of post-transcriptional regulation of functionally unrelated genes. Grouping human genes together along the genome sequence, or through long-range chromosome folding, is associated with reduced expression noise. Our results support the hypothesis that the selection for noise reduction is a major driver of the evolution of genome organisation. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - August 23, 2017 Category: Molecular Biology Authors: Kustatscher, G., Grabowski, P., Rappsilber, J. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology Articles Source Type: research
Network analyses identify liver-specific targets for treating liver diseases
In conclusion, we identified liver-specific genes linked to NAFLD pathogenesis, such as pyruvate kinase liver and red blood cell (PKLR), or to HCC pathogenesis, such as PKLR, patatin-like phospholipase domain containing 3 (PNPLA3), and proprotein convertase subtilisin/kexin type 9 (PCSK9), all of which are potential targets for drug development. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - August 21, 2017 Category: Molecular Biology Authors: Lee, S., Zhang, C., Liu, Z., Klevstig, M., Mukhopadhyay, B., Bergentall, M., Cinar, R., Stahlman, M., Sikanic, N., Park, J. K., Deshmukh, S., Harzandi, A. M., Kuijpers, T., Grotli, M., Elsässer, S. J., Piening, B. D., Snyder, M., Smith, U., Nielse Tags: Genome-Scale & Integrative Biology, Molecular Biology of Disease, Network Biology Articles Source Type: research
Improving the phenotype predictions of a yeast genome-scale metabolic model by incorporating enzymatic constraints
Genome-scale metabolic models (GEMs) are widely used to calculate metabolic phenotypes. They rely on defining a set of constraints, the most common of which is that the production of metabolites and/or growth are limited by the carbon source uptake rate. However, enzyme abundances and kinetics, which act as limitations on metabolic fluxes, are not taken into account. Here, we present GECKO, a method that enhances a GEM to account for enzymes as part of reactions, thereby ensuring that each metabolic flux does not exceed its maximum capacity, equal to the product of the enzyme's abundance and turnover number. We applied GEC...
Source: Molecular Systems Biology - August 3, 2017 Category: Molecular Biology Authors: Sanchez, B. J., Zhang, C., Nilsson, A., Lahtvee, P.-J., Kerkhoven, E. J., Nielsen, J. Tags: Genome-Scale & Integrative Biology, Metabolism, Methods & Resources Articles Source Type: research
