Determinants of RNA metabolism in the Schizosaccharomyces pombe genome
To decrypt the regulatory code of the genome, sequence elements must be defined that determine the kinetics of RNA metabolism and thus gene expression. Here, we attempt such decryption in an eukaryotic model organism, the fission yeast S. pombe. We first derive an improved genome annotation that redefines borders of 36% of expressed mRNAs and adds 487 non-coding RNAs (ncRNAs). We then combine RNA labeling in vivo with mathematical modeling to obtain rates of RNA synthesis and degradation for 5,484 expressed RNAs and splicing rates for 4,958 introns. We identify functional sequence elements in DNA and RNA tha...
Source: Molecular Systems Biology - February 16, 2016 Category: Molecular Biology Authors: Eser, P., Wachutka, L., Maier, K. C., Demel, C., Boroni, M., Iyer, S., Cramer, P., Gagneur, J. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, RNA Biology Articles Source Type: research
Orthogonal intercellular signaling for programmed spatial behavior
Bidirectional intercellular signaling is an essential feature of multicellular organisms, and the engineering of complex biological systems will require multiple pathways for intercellular signaling with minimal crosstalk. Natural quorum-sensing systems provide components for cell communication, but their use is often constrained by signal crosstalk. We have established new orthogonal systems for cell–cell communication using acyl homoserine lactone signaling systems. Quantitative measurements in contexts of differing receiver protein expression allowed us to separate different types of crosstalk between 3-oxo-C6- an...
Source: Molecular Systems Biology - January 25, 2016 Category: Molecular Biology Authors: Grant, P. K., Dalchau, N., Brown, J. R., Federici, F., Rudge, T. J., Yordanov, B., Patange, O., Phillips, A., Haseloff, J. Tags: Signal Transduction, Synthetic Biology & Biotechnology Articles Source Type: research
The interdependence of transcript and protein abundance: new data-new complexities
The relative contribution of transcriptional and translational regulation in gene expression control has been intensely debated and remains a challenging question. Recent reports have suggested that protein abundance in mammalian cells is primarily controlled at the transcript-level. In their recent work, Cheng et al (2016) determined the proteomic and transcriptomic changes in cells responding to endoplasmic reticulum (ER) stress. Their analyses indicate that the ER stress response is significantly controlled at both the transcript and protein levels. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - January 20, 2016 Category: Molecular Biology Authors: Liu, Y., Aebersold, R. Tags: Genome-Scale & Integrative Biology, Membrane & Intracellular Transport News [amp ] Views Source Type: research
Differential dynamics of the mammalian mRNA and protein expression response to misfolding stress
The relative importance of regulation at the mRNA versus protein level is subject to ongoing debate. To address this question in a dynamic system, we mapped proteomic and transcriptomic changes in mammalian cells responding to stress induced by dithiothreitol over 30 h. Specifically, we estimated the kinetic parameters for the synthesis and degradation of RNA and proteins, and deconvoluted the response patterns into common and unique to each regulatory level using a new statistical tool. Overall, the two regulatory levels were equally important, but differed in their impact on molecule concentrations. Both mRNA and pr...
Source: Molecular Systems Biology - January 20, 2016 Category: Molecular Biology Authors: Cheng, Z., Teo, G., Krueger, S., Rock, T. M., Koh, H. W., Choi, H., Vogel, C. Tags: Genome-Scale & Integrative Biology, Membrane & Intracellular Transport Articles Source Type: research
Antisense transcription as a tool to tune gene expression
A surprise that has emerged from transcriptomics is the prevalence of genomic antisense transcription, which occurs counter to gene orientation. While frequent, the roles of antisense transcription in regulation are poorly understood. We built a synthetic system in Escherichia coli to study how antisense transcription can change the expression of a gene and tune the response characteristics of a regulatory circuit. We developed a new genetic part that consists of a unidirectional terminator followed by a constitutive antisense promoter and demonstrate that this part represses gene expression proportionally to the antisense...
Source: Molecular Systems Biology - January 14, 2016 Category: Molecular Biology Authors: Brophy, J. A., Voigt, C. A. Tags: Quantitative Biology & Dynamical Systems, Synthetic Biology & Biotechnology, Transcription Articles Source Type: research
Regulation of alternative splicing at the single-cell level
Alternative splicing is a key cellular mechanism for generating distinct isoforms, whose relative abundances regulate critical cellular processes. It is therefore essential that inclusion levels of alternative exons be tightly regulated. However, how the precision of inclusion levels among individual cells is governed is poorly understood. Using single-cell gene expression, we show that the precision of inclusion levels of alternative exons is determined by the degree of evolutionary conservation at their flanking intronic regions. Moreover, the inclusion levels of alternative exons, as well as the expression levels of the...
Source: Molecular Systems Biology - December 28, 2015 Category: Molecular Biology Authors: Faigenbloom, L., Rubinstein, N. D., Kloog, Y., Mayrose, I., Pupko, T., Stein, R. Tags: Genome-Scale & Integrative Biology, RNA Biology Reports Source Type: research
Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation
Mammalian chromosomes fold into arrays of megabase-sized topologically associating domains (TADs), which are arranged into compartments spanning multiple megabases of genomic DNA. TADs have internal substructures that are often cell type specific, but their higher-order organization remains elusive. Here, we investigate TAD higher-order interactions with Hi-C through neuronal differentiation and show that they form a hierarchy of domains-within-domains (metaTADs) extending across genomic scales up to the range of entire chromosomes. We find that TAD interactions are well captured by tree-like, hierarchical structures irres...
Source: Molecular Systems Biology - December 23, 2015 Category: Molecular Biology Authors: Fraser, J., Ferrai, C., Chiariello, A. M., Schueler, M., Rito, T., Laudanno, G., Barbieri, M., Moore, B. L., Kraemer, D. C., Aitken, S., Xie, S. Q., Morris, K. J., Itoh, M., Kawaji, H., Jaeger, I., Hayashizaki, Y., Carninci, P., Forrest, A. R., The FANTOM Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Development & Differentiation, Genome-Scale & Integrative Biology Articles Source Type: research
A chemical-genetic interaction map of small molecules using high-throughput imaging in cancer cells
Small molecules often affect multiple targets, elicit off-target effects, and induce genotype-specific responses. Chemical genetics, the mapping of the genotype dependence of a small molecule's effects across a broad spectrum of phenotypes can identify novel mechanisms of action. It can also reveal unanticipated effects and could thereby reduce high attrition rates of small molecule development pipelines. Here, we used high-content screening and image analysis to measure effects of 1,280 pharmacologically active compounds on complex phenotypes in isogenic cancer cell lines which harbor activating or inactivating mutations ...
Source: Molecular Systems Biology - December 23, 2015 Category: Molecular Biology Authors: Breinig, M., Klein, F. A., Huber, W., Boutros, M. Tags: Genome-Scale & Integrative Biology, Pharmacology & Drug Discovery Articles Source Type: research
Image data in need of a home
Recognized public community databases for image data deposition have been lacking so far. New databases are emerging that provide a promising infrastructure for hosting and distributing high content imaging datasets. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - December 23, 2015 Category: Molecular Biology Authors: Lemberger, T. Tags: Editorial Source Type: research
The evolution of standards and data management practices in systems biology
(Source: Molecular Systems Biology)
Source: Molecular Systems Biology - December 23, 2015 Category: Molecular Biology Authors: Stanford, N. J., Wolstencroft, K., Golebiewski, M., Kania, R., Juty, N., Tomlinson, C., Owen, S., Butcher, S., Hermjakob, H., Le Novere, N., Mueller, W., Snoep, J., Goble, C. Tags: Methods & Resources Commentary Source Type: research
The BioStudies database
(Source: Molecular Systems Biology)
Source: Molecular Systems Biology - December 23, 2015 Category: Molecular Biology Authors: McEntyre, J., Sarkans, U., Brazma, A. Tags: Methods & Resources Commentary Source Type: research
The bimodally expressed microRNA miR-142 gates exit from pluripotency
A stem cell's decision to self-renew or differentiate is thought to critically depend on signaling cues provided by its environment. It is unclear whether stem cells have the intrinsic capacity to control their responsiveness to environmental signals that can be fluctuating and noisy. Using a novel single-cell microRNA activity reporter, we show that miR-142 is bimodally expressed in embryonic stem cells, creating two states indistinguishable by pluripotency markers. A combination of modeling and quantitative experimental data revealed that mESCs switch stochastically between the two miR-142 states. We find that cells with...
Source: Molecular Systems Biology - December 21, 2015 Category: Molecular Biology Authors: Sladitschek, H. L., Neveu, P. A. Tags: Development & Differentiation, Quantitative Biology & Dynamical Systems Articles Source Type: research
Fundamentals of protein interaction network mapping
Studying protein interaction networks of all proteins in an organism ("interactomes") remains one of the major challenges in modern biomedicine. Such information is crucial to understanding cellular pathways and developing effective therapies for the treatment of human diseases. Over the past two decades, diverse biochemical, genetic, and cell biological methods have been developed to map interactomes. In this review, we highlight basic principles of interactome mapping. Specifically, we discuss the strengths and weaknesses of individual assays, how to select a method appropriate for the problem being studied, and provide ...
Source: Molecular Systems Biology - December 17, 2015 Category: Molecular Biology Authors: Snider, J., Kotlyar, M., Saraon, P., Yao, Z., Jurisica, I., Stagljar, I. Tags: Genome-Scale & Integrative Biology, Post-translational Modifications, Proteolysis & Proteomics Reviews Source Type: research
Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers
Genetic mechanisms underlying abnormal early neural development in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi-tissue study demonstrated high expression of many of the same gene networks between blood and brain tissues, in particular with cell cycle functions. We explored relationships between blood gene expression and total brain volume (TBV) in 142 ASD and control male toddlers. In control toddlers, TBV variation significantly correlated with cell cycle and...
Source: Molecular Systems Biology - December 14, 2015 Category: Molecular Biology Authors: Pramparo, T., Lombardo, M. V., Campbell, K., Barnes, C. C., Marinero, S., Solso, S., Young, J., Mayo, M., Dale, A., Ahrens-Barbeau, C., Murray, S. S., Lopez, L., Lewis, N., Pierce, K., Courchesne, E. Tags: Development & Differentiation, Network Biology, Neuroscience Articles Source Type: research
A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression
Large-scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome-scale, gain-of-function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that ...
Source: Molecular Systems Biology - December 11, 2015 Category: Molecular Biology Authors: Shields, B. B., Pecot, C. V., Gao, H., McMillan, E., Potts, M., Nagel, C., Purinton, S., Wang, Y., Ivan, C., Kim, H. S., Borkowski, R. J., Khan, S., Rodriguez-Aguayo, C., Lopez-Berestein, G., Lea, J., Gazdar, A., Baggerly, K. A., Sood, A. K., White, M. A. Tags: Cancer, Chromatin, Epigenetics, Genomics & Functional Genomics Articles Source Type: research
