Unlocking the chromatin code by deciphering protein-DNA interactions
Characterizing the composition of protein complexes bound to different genomic loci is essential for advancing our mechanistic understanding of transcriptional regulation. In their recent study, Krijgsveld and colleagues (Rafiee et al, 2016) report ChIP-SICAP, a powerful tool for deciphering the chromatin proteome by combining chromatin immunoprecipitation, selective isolation of chromatin-associated proteins and mass spectrometry. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - November 9, 2016 Category: Molecular Biology Authors: Bensaddek, D., Lamond, A. I. Tags: Methods & Resources, Post-translational Modifications, Proteolysis & Proteomics, Transcription News [amp ] Views Source Type: research
Dynamical compensation in physiological circuits
We present a class of circuits that show DC by means of a nonlinear feedback loop in which the regulated variable controls the functional mass of the controlling endocrine or neuronal tissue. This mechanism applies to the control of blood glucose by insulin and explains several experimental observations on insulin resistance. We provide evidence that this mechanism may also explain compensation and organ size control in other physiological circuits. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - November 7, 2016 Category: Molecular Biology Authors: Karin, O., Swisa, A., Glaser, B., Dor, Y., Alon, U. Tags: Metabolism, Molecular Biology of Disease, Quantitative Biology & Dynamical Systems Reports Source Type: research
A gene-centered C. elegans protein-DNA interaction network provides a framework for functional predictions
Transcription factors (TFs) play a central role in controlling spatiotemporal gene expression and the response to environmental cues. A comprehensive understanding of gene regulation requires integrating physical protein–DNA interactions (PDIs) with TF regulatory activity, expression patterns, and phenotypic data. Although great progress has been made in mapping PDIs using chromatin immunoprecipitation, these studies have only characterized ~10% of TFs in any metazoan species. The nematode C. elegans has been widely used to study gene regulation due to its compact genome with short regulatory sequences. Here, we...
Source: Molecular Systems Biology - October 23, 2016 Category: Molecular Biology Authors: Fuxman Bass, J. I., Pons, C., Kozlowski, L., Reece-Hoyes, J. S., Shrestha, S., Holdorf, A. D., Mori, A., Myers, C. L., Walhout, A. J. Tags: Genome-Scale & Integrative Biology, Network Biology, Transcription Articles Source Type: research
Quantifying gene expression: the importance of being subtle
Gene expression is regulated at both the mRNA and protein level through on-off switches and fine-tuned control. In their recent study, Edfors et al (2016) use highly accurate, targeted proteomics methods and examine to what extent the amount of protein produced per mRNA transcript varies across different tissues. They find that the bulk part of protein concentrations is set at a per-gene level: This relationship, the protein/mRNA ratio, is constant across cell types and tissues, but varies by several orders of magnitude across genes. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - October 19, 2016 Category: Molecular Biology Authors: Silva, G. M., Vogel, C. Tags: Genome-Scale & Integrative Biology, Post-translational Modifications, Proteolysis & Proteomics, Transcription News [amp ] Views Source Type: research
Gene-specific correlation of RNA and protein levels in human cells and tissues
In conclusion, our data suggest that transcriptome analysis can be used as a tool to predict the protein copy numbers per cell, thus forming an attractive link between the field of genomics and proteomics. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - October 19, 2016 Category: Molecular Biology Authors: Edfors, F., Danielsson, F., Hallström, B. M., Käll, L., Lundberg, E., Ponten, F., Forsström, B., Uhlen, M. Tags: Genome-Scale & Integrative Biology, Post-translational Modifications, Proteolysis & Proteomics, Transcription Articles Source Type: research
Bacterial persistence is an active {sigma}S stress response to metabolic flux limitation
While persisters are a health threat due to their transient antibiotic tolerance, little is known about their phenotype and what actually causes persistence. Using a new method for persister generation and high-throughput methods, we comprehensively mapped the molecular phenotype of Escherichia coli during the entry and in the state of persistence in nutrient-rich conditions. The persister proteome is characterized by S-mediated stress response and a shift to catabolism, a proteome that starved cells tried to but could not reach due to absence of a carbon and energy source. Metabolism of persisters is geared toward energy ...
Source: Molecular Systems Biology - September 20, 2016 Category: Molecular Biology Authors: Radzikowski, J. L., Vedelaar, S., Siegel, D., Ortega, A. D., Schmidt, A., Heinemann, M. Tags: Metabolism, Microbiology, Virology & Host Pathogen Interaction, Quantitative Biology & Dynamical Systems Articles Source Type: research
Cytometry-based single-cell analysis of intact epithelial signaling reveals MAPK activation divergent from TNF-{alpha}-induced apoptosis in vivo
(Source: Molecular Systems Biology)
Source: Molecular Systems Biology - August 28, 2016 Category: Molecular Biology Authors: Simmons, A. J., Banerjee, A., McKinley, E. T., Scurrah, C. R., Herring, C. A., Gewin, L. S., Masuzaki, R., Karp, S. J., Franklin, J. L., Gerdes, M. J., Irish, J. M., Coffey, R. J., Lau, K. S. Tags: Corrigendum Source Type: research
Frequency-dependent selection: a diversifying force in microbial populations
The benefits of "bet-hedging" strategies have been assumed to be the main cause of phenotypic diversity in biological populations. However, in their recent work, Healey et al (2016) provide experimental support for negative frequency-dependent selection (NFDS) as an alternative driving force of diversity. NFDS favors rare phenotypes over common ones, resulting in an evolutionarily stable mixture of phenotypes that is not necessarily optimal for population growth. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - August 2, 2016 Category: Molecular Biology Authors: Charlebois, D. A., Balazsi, G. Tags: Evolution, Microbiology, Virology & Host Pathogen Interaction, Quantitative Biology & Dynamical Systems News [amp ] Views Source Type: research
Negative frequency-dependent interactions can underlie phenotypic heterogeneity in a clonal microbial population
Genetically identical cells in microbial populations often exhibit a remarkable degree of phenotypic heterogeneity even in homogenous environments. Such heterogeneity is commonly thought to represent a bet-hedging strategy against environmental uncertainty. However, evolutionary game theory predicts that phenotypic heterogeneity may also be a response to negative frequency-dependent interactions that favor rare phenotypes over common ones. Here we provide experimental evidence for this alternative explanation in the context of the well-studied yeast GAL network. In an environment containing the two sugars glucose and ...
Source: Molecular Systems Biology - August 2, 2016 Category: Molecular Biology Authors: Healey, D., Axelrod, K., Gore, J. Tags: Evolution, Microbiology, Virology & Host Pathogen Interaction, Quantitative Biology & Dynamical Systems Articles Source Type: research
Parallel reverse genetic screening in mutant human cells using transcriptomics
Reverse genetic screens have driven gene annotation and target discovery in model organisms. However, many disease-relevant genotypes and phenotypes cannot be studied in lower organisms. It is therefore essential to overcome technical hurdles associated with large-scale reverse genetics in human cells. Here, we establish a reverse genetic approach based on highly robust and sensitive multiplexed RNA sequencing of mutant human cells. We conduct 10 parallel screens using a collection of engineered haploid isogenic cell lines with knockouts covering tyrosine kinases and identify known and unexpected effects on signaling pathw...
Source: Molecular Systems Biology - July 31, 2016 Category: Molecular Biology Authors: Gapp, B. V., Konopka, T., Penz, T., Dalal, V., Bürckstümmer, T., Bock, C., Nijman, S. M. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Methods & Resources Reports Source Type: research
Deep learning for computational biology
Technological advances in genomics and imaging have led to an explosion of molecular and cellular profiling data from large numbers of samples. This rapid increase in biological data dimension and acquisition rate is challenging conventional analysis strategies. Modern machine learning methods, such as deep learning, promise to leverage very large data sets for finding hidden structure within them, and for making accurate predictions. In this review, we discuss applications of this new breed of analysis approaches in regulatory genomics and cellular imaging. We provide background of what deep learning is, and the settings ...
Source: Molecular Systems Biology - July 28, 2016 Category: Molecular Biology Authors: Angermueller, C., Pärnamaa, T., Parts, L., Stegle, O. Tags: Computational Biology Review Source Type: research
Co-recruitment analysis of the CBL and CBLB signalosomes in primary T cells identifies CD5 as a key regulator of TCR-induced ubiquitylation
T-cell receptor (TCR) signaling is essential for the function of T cells and negatively regulated by the E3 ubiquitin–protein ligases CBL and CBLB. Here, we combined mouse genetics and affinity purification coupled to quantitative mass spectrometry to monitor the dynamics of the CBL and CBLB signaling complexes that assemble in normal T cells over 600 seconds of TCR stimulation. We identify most previously known CBL and CBLB interacting partners, as well as a majority of proteins that have not yet been implicated in those signaling complexes. We exploit correlations in protein association with CBL and CBLB as a ...
Source: Molecular Systems Biology - July 28, 2016 Category: Molecular Biology Authors: Voisinne, G., Garcia-Blesa, A., Chaoui, K., Fiore, F., Bergot, E., Girard, L., Malissen, M., Burlet-Schiltz, O., Gonzalez de Peredo, A., Malissen, B., Roncagalli, R. Tags: Immunology, Post-translational Modifications, Proteolysis & Proteomics, Signal Transduction Articles Source Type: research
Pervasive isoform-specific translational regulation via alternative transcription start sites in mammals
Transcription initiated at alternative sites can produce mRNA isoforms with different 5'UTRs, which are potentially subjected to differential translational regulation. However, the prevalence of such isoform-specific translational control across mammalian genomes is currently unknown. By combining polysome profiling with high-throughput mRNA 5' end sequencing, we directly measured the translational status of mRNA isoforms with distinct start sites. Among 9,951 genes expressed in mouse fibroblasts, we identified 4,153 showed significant initiation at multiple sites, of which 745 genes exhibited significant isoform-divergent...
Source: Molecular Systems Biology - July 17, 2016 Category: Molecular Biology Authors: Wang, X., Hou, J., Quedenau, C., Chen, W. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Protein Biosynthesis & Quality Control Articles Source Type: research
Strand-specific, high-resolution mapping of modified RNA polymerase II
Reversible modification of the RNAPII C-terminal domain links transcription with RNA processing and surveillance activities. To better understand this, we mapped the location of RNAPII carrying the five types of CTD phosphorylation on the RNA transcript, providing strand-specific, nucleotide-resolution information, and we used a machine learning-based approach to define RNAPII states. This revealed enrichment of Ser5P, and depletion of Tyr1P, Ser2P, Thr4P, and Ser7P in the transcription start site (TSS) proximal ~150 nt of most genes, with depletion of all modifications close to the poly(A) site. The TSS region also showed...
Source: Molecular Systems Biology - June 9, 2016 Category: Molecular Biology Authors: Milligan, L., Huynh-Thu, V. A., Delan-Forino, C., Tuck, A., Petfalski, E., Lombrana, R., Sanguinetti, G., Kudla, G., Tollervey, D. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Methods & Resources, Transcription Articles Source Type: research
Multistability and dynamic transitions of intracellular Min protein patterns
Cells owe their internal organization to self-organized protein patterns, which originate and adapt to growth and external stimuli via a process that is as complex as it is little understood. Here, we study the emergence, stability, and state transitions of multistable Min protein oscillation patterns in live Escherichia coli bacteria during growth up to defined large dimensions. De novo formation of patterns from homogenous starting conditions is observed and studied both experimentally and in simulations. A new theoretical approach is developed for probing pattern stability under perturbations. Quantitative experiments a...
Source: Molecular Systems Biology - June 7, 2016 Category: Molecular Biology Authors: Wu, F., Halatek, J., Reiter, M., Kingma, E., Frey, E., Dekker, C. Tags: Development & Differentiation, Quantitative Biology & Dynamical Systems Articles Source Type: research
