From intracellular signaling to population oscillations: bridging size- and time-scales in collective behavior
Collective behavior in cellular populations is coordinated by biochemical signaling networks within individual cells. Connecting the dynamics of these intracellular networks to the population phenomena they control poses a considerable challenge because of network complexity and our limited knowledge of kinetic parameters. However, from physical systems, we know that behavioral changes in the individual constituents of a collectively behaving system occur in a limited number of well-defined classes, and these can be described using simple models. Here, we apply such an approach to the emergence of collective oscillations i...
Source: Molecular Systems Biology - January 23, 2015 Category: Molecular Biology Authors: Sgro, A. E., Schwab, D. J., Noorbakhsh, J., Mestler, T., Mehta, P., Gregor, T. Tags: Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Changing partners: transcription factors form different complexes on and off chromatin
The current knowledge on how protein–protein interactions regulate the function of transcription factors (TFs) has remained limited due to an incomplete knowledge of their interaction partners. In their recent work, Chen and colleagues (Li et al, 2015) analyse the interactome of 56 TFs and reveal distinct chromatin-associated and soluble TF complexes. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - January 21, 2015 Category: Molecular Biology Authors: Ji, Z., Sharrocks, A. D. Tags: Network Biology, Post-translational Modifications, Proteolysis & Proteomics, Transcription News and Views Source Type: research
Defining a minimal cell: essentiality of small ORFs and ncRNAs in a genome-reduced bacterium
Identifying all essential genomic components is critical for the assembly of minimal artificial life. In the genome-reduced bacterium Mycoplasma pneumoniae, we found that small ORFs (smORFs; < 100 residues), accounting for 10% of all ORFs, are the most frequently essential genomic components (53%), followed by conventional ORFs (49%). Essentiality of smORFs may be explained by their function as members of protein and/or DNA/RNA complexes. In larger proteins, essentiality applied to individual domains and not entire proteins, a notion we could confirm by expression of truncated domains. The fraction of essential non...
Source: Molecular Systems Biology - January 21, 2015 Category: Molecular Biology Authors: Lluch-Senar, M., Delgado, J., Chen, W.-H., Llorens-Rico, V., O'Reilly, F. J., Wodke, J. A., Unal, E. B., Yus, E., Martinez, S., Nichols, R. J., Ferrar, T., Vivancos, A., Schmeisky, A., Stulke, J., van Noort, V., Gavin, A.-C., Bork, P., Serrano, L. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology Reports Source Type: research
Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes
The current knowledge on how transcription factors (TFs), the ultimate targets and executors of cellular signalling pathways, are regulated by protein–protein interactions remains limited. Here, we performed proteomics analyses of soluble and chromatin-associated complexes of 56 TFs, including the targets of many signalling pathways involved in development and cancer, and 37 members of the Forkhead box (FOX) TF family. Using tandem affinity purification followed by mass spectrometry (TAP/MS), we performed 214 purifications and identified 2,156 high-confident protein–protein interactions. We found that most TFs ...
Source: Molecular Systems Biology - January 21, 2015 Category: Molecular Biology Authors: Li, X., Wang, W., Wang, J., Malovannaya, A., Xi, Y., Li, W., Guerra, R., Hawke, D. H., Qin, J., Chen, J. Tags: Network Biology, Post-translational Modifications, Proteolysis & Proteomics, Transcription Articles Source Type: research
Essential gene disruptions reveal complex relationships between phenotypic robustness, pleiotropy, and fitness
The concept of robustness in biology has gained much attention recently, but a mechanistic understanding of how genetic networks regulate phenotypic variation has remained elusive. One approach to understand the genetic architecture of variability has been to analyze dispensable gene deletions in model organisms; however, the most important genes cannot be deleted. Here, we have utilized two systems in yeast whereby essential genes have been altered to reduce expression. Using high-throughput microscopy and image analysis, we have characterized a large number of morphological phenotypes, and their associated variation, for...
Source: Molecular Systems Biology - January 21, 2015 Category: Molecular Biology Authors: Bauer, C. R., Li, S., Siegal, M. L. Tags: Genome-Scale & Integrative Biology Articles Source Type: research
Linked circadian outputs control elongation growth and flowering in response to photoperiod and temperature
Clock-regulated pathways coordinate the response of many developmental processes to changes in photoperiod and temperature. We model two of the best-understood clock output pathways in Arabidopsis, which control key regulators of flowering and elongation growth. In flowering, the model predicted regulatory links from the clock to CYCLING DOF FACTOR 1 (CDF1) and FLAVIN-BINDING, KELCH REPEAT, F-BOX 1 (FKF1) transcription. Physical interaction data support these links, which create threefold feed-forward motifs from two clock components to the floral regulator FT. In hypocotyl growth, the model described clock-regulated trans...
Source: Molecular Systems Biology - January 19, 2015 Category: Molecular Biology Authors: Seaton, D. D., Smith, R. W., Song, Y. H., MacGregor, D. R., Stewart, K., Steel, G., Foreman, J., Penfield, S., Imaizumi, T., Millar, A. J., Halliday, K. J. Tags: Plant Biology, Quantitative Biology & Dynamical Systems Articles Source Type: research
Genome-wide study of mRNA degradation and transcript elongation in Escherichia coli
An essential part of gene expression is the coordination of RNA synthesis and degradation, which occurs in the same cellular compartment in bacteria. Here, we report a genome-wide RNA degradation study in Escherichia coli using RNA-seq, and present evidence that the stereotypical exponential RNA decay curve obtained using initiation inhibitor, rifampicin, consists of two phases: residual RNA synthesis, a delay in the interruption of steady state that is dependent on distance relative to the mRNA's 5' end, and the exponential decay. This gives a more accurate RNA lifetime and RNA polymerase elongation rate simultaneously ge...
Source: Molecular Systems Biology - January 12, 2015 Category: Molecular Biology Authors: Chen, H., Shiroguchi, K., Ge, H., Xie, X. S. Tags: Quantitative Biology & Dynamical Systems, RNA Biology Articles Source Type: research
A high-throughput ChIP-Seq for large-scale chromatin studies
We present a modified approach of chromatin immuno-precipitation followed by sequencing (ChIP-Seq), which relies on the direct ligation of molecular barcodes to chromatin fragments, thereby permitting experimental scale-up. With Bar-ChIP now enabling the concurrent profiling of multiple DNA–protein interactions, we report the simultaneous generation of 90 ChIP-Seq datasets without any robotic instrumentation. We demonstrate that application of Bar-ChIP to a panel of Saccharomyces cerevisiae chromatin-associated mutants provides a rapid and accurate genome-wide overview of their chromatin status. Additionally, we vali...
Source: Molecular Systems Biology - January 12, 2015 Category: Molecular Biology Authors: Chabbert, C. D., Adjalley, S. H., Klaus, B., Fritsch, E. S., Gupta, I., Pelechano, V., Steinmetz, L. M. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Methods & Resources Articles Source Type: research
Deciphering preferential interactions within supramolecular protein complexes: the proteasome case
In eukaryotic cells, intracellular protein breakdown is mainly performed by the ubiquitin–proteasome system. Proteasomes are supramolecular protein complexes formed by the association of multiple sub-complexes and interacting proteins. Therefore, they exhibit a very high heterogeneity whose function is still not well understood. Here, using a newly developed method based on the combination of affinity purification and protein correlation profiling associated with high-resolution mass spectrometry, we comprehensively characterized proteasome heterogeneity and identified previously unknown preferential associations wit...
Source: Molecular Systems Biology - January 5, 2015 Category: Molecular Biology Authors: Fabre, B., Lambour, T., Garrigues, L., Amalric, F., Vigneron, N., Menneteau, T., Stella, A., Monsarrat, B., Van den Eynde, B., Burlet-Schiltz, O., Bousquet-Dubouch, M.-P. Tags: Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Autism cornered: network analyses reveal mechanisms of autism spectrum disorders
Despite a wealth of behavioral, cognitive, biological, and genetic studies, the causes of autism have remained largely unknown. In their recent work, Snyder and colleagues (Li et al, 2014) use a systems biology approach and shed light on the molecular and cellular mechanisms underlying autism, thus opening novel avenues for understanding the disease and developing potential treatments. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - December 30, 2014 Category: Molecular Biology Authors: Auffray, C. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Network Biology News [amp ] Views Source Type: research
Integrated systems analysis reveals a molecular network underlying autism spectrum disorders
Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, ...
Source: Molecular Systems Biology - December 30, 2014 Category: Molecular Biology Authors: Li, J., Shi, M., Ma, Z., Zhao, S., Euskirchen, G., Ziskin, J., Urban, A., Hallmayer, J., Snyder, M. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Network Biology Articles Source Type: research
ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma
Treatment of BRAF mutant melanomas with specific BRAF inhibitors leads to tumor remission. However, most patients eventually relapse due to drug resistance. Therefore, we designed an integrated strategy using (phospho)proteomic and functional genomic platforms to identify drug targets whose inhibition sensitizes melanoma cells to BRAF inhibition. We found many proteins to be induced upon PLX4720 (BRAF inhibitor) treatment that are known to be involved in BRAF inhibitor resistance, including FOXD3 and ErbB3. Several proteins were down-regulated, including Rnd3, a negative regulator of ROCK1 kinase. For our genomic approach,...
Source: Molecular Systems Biology - December 23, 2014 Category: Molecular Biology Authors: Smit, M. A., Maddalo, G., Greig, K., Raaijmakers, L. M., Possik, P. A., van Breukelen, B., Cappadona, S., Heck, A. J., Altelaar, A. M., Peeper, D. S. Tags: Cancer, Genome-Scale & Integrative Biology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Causal signals between codon bias, mRNA structure, and the efficiency of translation and elongation
We present a robust method to extract codon translation rates and protein synthesis rates from these data, and identify causal features associated with elongation and translation efficiency in physiological conditions in yeast. We show that neither elongation rate nor translational efficiency is improved by experimental manipulation of the abundance or body sequence of the rare AGG tRNA. Deletion of three of the four copies of the heavily used ACA tRNA shows a modest efficiency decrease that could be explained by other rate-reducing signals at gene start. This suggests that correlation between codon bias and efficiency ari...
Source: Molecular Systems Biology - December 23, 2014 Category: Molecular Biology Authors: Pop, C., Rouskin, S., Ingolia, N. T., Han, L., Phizicky, E. M., Weissman, J. S., Koller, D. Tags: Computational Biology, Genome-Scale & Integrative Biology Articles Source Type: research
Loss of growth homeostasis by genetic decoupling of cell division from biomass growth: implication for size control mechanisms
We describe genetic manipulations that decouple cell division from cell size, leading to the loss of growth homeostasis, with cells becoming progressively smaller or progressively larger until arresting. This was achieved by modulating glucose influx independently of external glucose. Division rate followed glucose influx, while volume growth was largely defined by external glucose. Therefore, the coordination of size and division observed in wild-type cells reflects tuning of two parallel processes, which is only refined by an inherent feedback-dependent coupling. We present a class of size control models explaining the o...
Source: Molecular Systems Biology - December 23, 2014 Category: Molecular Biology Authors: Schmidt-Glenewinkel, H., Barkai, N. Tags: Cell Cycle, Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Annotation of genomics data using bidirectional hidden Markov models unveils variations in Pol II transcription cycle
DNA replication, transcription and repair involve the recruitment of protein complexes that change their composition as they progress along the genome in a directed or strand-specific manner. Chromatin immunoprecipitation in conjunction with hidden Markov models (HMMs) has been instrumental in understanding these processes, as they segment the genome into discrete states that can be related to DNA-associated protein complexes. However, current HMM-based approaches are not able to assign forward or reverse direction to states or properly integrate strand-specific (e.g., RNA expression) with non-strand-specific (e.g., ChIP) ...
Source: Molecular Systems Biology - December 19, 2014 Category: Molecular Biology Authors: Zacher, B., Lidschreiber, M., Cramer, P., Gagneur, J., Tresch, A. Tags: Computational Biology, Transcription Articles Source Type: research
