Forces driving the three-dimensional folding of eukaryotic genomes
The last decade has radically renewed our understanding of higher order chromatin folding in the eukaryotic nucleus. As a result, most current models are in support of a mostly hierarchical and relatively stable folding of chromosomes dividing chromosomal territories into A- (active) and B- (inactive) compartments, which are then further partitioned into topologically associating domains (TADs), each of which is made up from multiple loops stabilized mainly by the CTCF and cohesin chromatin-binding complexes. Nonetheless, the structure-to-function relationship of eukaryotic genomes is still not well understood. Here, we fo...
Source: Molecular Systems Biology - June 1, 2018 Category: Molecular Biology Authors: Rada-Iglesias, A., Grosveld, F. G., Papantonis, A. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Transcription Reviews Source Type: research
Mapping DNA damage-dependent genetic interactions in yeast via party mating and barcode fusion genetics
Condition-dependent genetic interactions can reveal functional relationships between genes that are not evident under standard culture conditions. State-of-the-art yeast genetic interaction mapping, which relies on robotic manipulation of arrays of double-mutant strains, does not scale readily to multi-condition studies. Here, we describe barcode fusion genetics to map genetic interactions (BFG-GI), by which double-mutant strains generated via en masse "party" mating can also be monitored en masse for growth to detect genetic interactions. By using site-specific recombination to fuse two DNA barcodes, each representing a s...
Source: Molecular Systems Biology - May 28, 2018 Category: Molecular Biology Authors: Diaz-Mejia, J. J., Celaj, A., Mellor, J. C., Cote, A., Balint, A., Ho, B., Bansal, P., Shaeri, F., Gebbia, M., Weile, J., Verby, M., Karkhanina, A., Zhang, Y., Wong, C., Rich, J., Prendergast, D., Gupta, G., Öztürk, S., Durocher, D., Brown Tags: Genome-Scale & Integrative Biology, Methods & Resources, Network Biology Source Type: research
High-throughput discovery of functional disordered regions
Partially or fully intrinsically disordered proteins are widespread in eukaryotic proteomes and play important biological functions. With the recognition that well defined protein structure is not a fundamental requirement for function come novel challenges, such as assigning function to disordered regions. In their recent work, Babu and colleagues (Ravarani et al, 2018) took on this challenge by developing IDR-Screen, a robust high-throughput approach for identifying functions of disordered regions. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - May 22, 2018 Category: Molecular Biology Authors: Ali, M., Ivarsson, Y. Tags: Genome-Scale & Integrative Biology, Structural Biology, Transcription News [amp ] Views Source Type: research
Learning lessons in sepsis from the children
Sepsis research has had relatively limited therapeutic success so far. In their recent study, Kobzik and colleagues (Joachim et al, 2018) identify novel drug-sensitive pathways in sepsis, derived exclusively from patient data. Their strategy is based on the analysis of a naturally sepsis-resistant population (pre-puberty children) and on the implementation of a novel-rich Pathway Drug Network, constructed from human gene expression data enriched in drug–pathway–gene clusters. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - May 17, 2018 Category: Molecular Biology Authors: Timmermans, S., Libert, C. Tags: Network Biology, Pharmacology & Drug Discovery, Systems Medicine News [amp ] Views Source Type: research
The relative resistance of children to sepsis mortality: from pathways to drug candidates
Attempts to develop drugs that address sepsis based on leads developed in animal models have failed. We sought to identify leads based on human data by exploiting a natural experiment: the relative resistance of children to mortality from severe infections and sepsis. Using public datasets, we identified key differences in pathway activity (Pathprint) in blood transcriptome profiles of septic adults and children. To find drugs that could promote beneficial (child) pathways or inhibit harmful (adult) ones, we built an in silico pathway drug network (PDN) using expression correlation between drug, disease, and pathway gene s...
Source: Molecular Systems Biology - May 17, 2018 Category: Molecular Biology Authors: Joachim, R. B., Altschuler, G. M., Hutchinson, J. N., Wong, H. R., Hide, W. A., Kobzik, L. Tags: Network Biology, Pharmacology & Drug Discovery, Systems Medicine Articles Source Type: research
High-throughput discovery of functional disordered regions: investigation of transactivation domains
We present IDR-Screen, a framework to discover functional IDRs in a high-throughput manner by simultaneously assaying large numbers of DNA sequences that code for short disordered sequences. Functionality-conferring patterns in their protein sequence are inferred through statistical learning. Using yeast HSF1 transcription factor-based assay, we discovered IDRs that function as transactivation domains (TADs) by screening a random sequence library and a designed library consisting of variants of 13 diverse TADs. Using machine learning, we find that segments devoid of positively charged residues but with redundant short sequ...
Source: Molecular Systems Biology - May 14, 2018 Category: Molecular Biology Authors: Ravarani, C. N., Erkina, T. Y., De Baets, G., Dudman, D. C., Erkine, A. M., Babu, M. M. Tags: Genome-Scale & Integrative Biology, Structural Biology, Transcription Articles Source Type: research
Expression variation and covariation impair analog and enable binary signaling control
Due to noise in the synthesis and degradation of proteins, the concentrations of individual vertebrate signaling proteins were estimated to vary with a coefficient of variation (CV) of approximately 25% between cells. Such high variation is beneficial for population-level regulation of cell functions but abolishes accurate single-cell signal transmission. Here, we measure cell-to-cell variability of relative protein abundance using quantitative proteomics of individual Xenopus laevis eggs and cultured human cells and show that variation is typically much lower, in the range of 5–15%, compatible with accurate single-c...
Source: Molecular Systems Biology - May 14, 2018 Category: Molecular Biology Authors: Kovary, K. M., Taylor, B., Zhao, M. L., Teruel, M. N. Tags: Quantitative Biology & Dynamical Systems, Signal Transduction, Transcription Articles Source Type: research
Computer-aided biochemical programming of synthetic microreactors as diagnostic devices
Biological systems have evolved efficient sensing and decision-making mechanisms to maximize fitness in changing molecular environments. Synthetic biologists have exploited these capabilities to engineer control on information and energy processing in living cells. While engineered organisms pose important technological and ethical challenges, de novo assembly of non-living biomolecular devices could offer promising avenues toward various real-world applications. However, assembling biochemical parts into functional information processing systems has remained challenging due to extensive multidimensional parameter spaces t...
Source: Molecular Systems Biology - April 26, 2018 Category: Molecular Biology Authors: Courbet, A., Amar, P., Fages, F., Renard, E., Molina, F. Tags: Quantitative Biology & Dynamical Systems, Synthetic Biology & Biotechnology Articles Source Type: research
Timing of gene expression in a cell-fate decision system
During development, morphogens provide extracellular cues allowing cells to select a specific fate by inducing complex transcriptional programs. The mating pathway in budding yeast offers simplified settings to understand this process. Pheromone secreted by the mating partner triggers the activity of a MAPK pathway, which results in the expression of hundreds of genes. Using a dynamic expression reporter, we quantified the kinetics of gene expression in single cells upon exogenous pheromone stimulation and in the physiological context of mating. In both conditions, we observed striking differences in the timing of inductio...
Source: Molecular Systems Biology - April 25, 2018 Category: Molecular Biology Authors: Aymoz, D., Sole, C., Pierre, J.-J., Schmitt, M., de Nadal, E., Posas, F., Pelet, S. Tags: Quantitative Biology & Dynamical Systems, Signal Transduction, Transcription Articles Source Type: research
Using single-cell genomics to understand developmental processes and cell fate decisions
High-throughput -omics techniques have revolutionised biology, allowing for thorough and unbiased characterisation of the molecular states of biological systems. However, cellular decision-making is inherently a unicellular process to which "bulk" -omics techniques are poorly suited, as they capture ensemble averages of cell states. Recently developed single-cell methods bridge this gap, allowing high-throughput molecular surveys of individual cells. In this review, we cover core concepts of analysis of single-cell gene expression data and highlight areas of developmental biology where single-cell techniques have made impo...
Source: Molecular Systems Biology - April 16, 2018 Category: Molecular Biology Authors: Griffiths, J. A., Scialdone, A., Marioni, J. C. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Development & Differentiation, Genome-Scale & Integrative Biology Reviews Source Type: research
Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling
Populations of isogenic cells often respond coherently to signals, despite differences in protein abundance and cell state. Previously, we uncovered processes in the Saccharomyces cerevisiae pheromone response system (PRS) that reduced cell-to-cell variability in signal strength and cellular response. Here, we screened 1,141 non-essential genes to identify 50 "variability genes". Most had distinct, separable effects on strength and variability of the PRS, defining these quantities as genetically distinct "axes" of system behavior. Three genes affected cytoplasmic microtubule function: BIM1, GIM2, and GIM4. We used genetic ...
Source: Molecular Systems Biology - April 4, 2018 Category: Molecular Biology Authors: Pesce, C. G., Zdraljevic, S., Peria, W. J., Bush, A., Repetto, M. V., Rockwell, D., Yu, R. C., Colman-Lerner, A., Brent, R. Tags: Cell Adhesion, Polarity & Cytoskeleton, Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Partnering with Life Science Alliance
Molecular Systems Biology is partnering with the new open-access journal Life Science Alliance, an initiative by three major not-for-profit science organizations. An informed transfer process was established with our partner to provide authors with clear editorial commitments and reduce the overall burden on reviewers. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - April 3, 2018 Category: Molecular Biology Authors: Lemberger, T. Tags: Editorial Source Type: research
High-resolution definition of humoral immune response correlates of effective immunity against HIV
We report advances in a humoral immunoprofiling approach and its application to elucidate hallmarks of effective HIV-1 viral control. Systematic serological analysis for a cohort of HIV-infected subjects with varying viral control was conducted using both a high-resolution, high-throughput biophysical antibody profiling approach, providing unbiased dissection of the humoral response, along with functional antibody assays, characterizing antibody-directed effector functions such as complement fixation and phagocytosis that are central to protective immunity. Profiles of subjects with varying viral control were computational...
Source: Molecular Systems Biology - March 26, 2018 Category: Molecular Biology Authors: Alter, G., Dowell, K. G., Brown, E. P., Suscovich, T. J., Mikhailova, A., Mahan, A. E., Walker, B. D., Nimmerjahn, F., Bailey-Kellogg, C., Ackerman, M. E. Tags: Genome-Scale & Integrative Biology, Immunology, Systems Medicine Articles Source Type: research
Transcriptional regulatory networks underlying gene expression changes in Huntington's disease
Transcriptional changes occur presymptomatically and throughout Huntington's disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD. We reconstructed a genome-scale model for the target genes of 718 transcription factors (TFs) in the mouse striatum by integrating a model of genomic binding sites with transcriptome profiling of striatal tissue from HD mouse models. We identified 48 differentially expressed TF-target gene modules associated with age- and CAG repeat length-dependent gene expression changes in Htt CAG knock-in mouse striatum and replicated many of these associations in independe...
Source: Molecular Systems Biology - March 26, 2018 Category: Molecular Biology Authors: Ament, S. A., Pearl, J. R., Cantle, J. P., Bragg, R. M., Skene, P. J., Coffey, S. R., Bergey, D. E., Wheeler, V. C., MacDonald, M. E., Baliga, N. S., Rosinski, J., Hood, L. E., Carroll, J. B., Price, N. D. Tags: Genome-Scale & Integrative Biology, Molecular Biology of Disease, Network Biology Articles Source Type: research
Systematic characterization of pan-cancer mutation clusters
Cancer genome sequencing has shown that driver genes can often be distinguished not only by the elevated mutation frequency but also by specific nucleotide positions that accumulate changes at a high rate. However, properties associated with a residue's potential to drive tumorigenesis when mutated have not yet been systematically investigated. Here, using a novel methodological approach, we identify and characterize a compendium of 180 hotspot residues within 160 human proteins which occur with a significant frequency and are likely to have functionally relevant impact. We find that such mutations (i) are more prominent i...
Source: Molecular Systems Biology - March 23, 2018 Category: Molecular Biology Authors: Buljan, M., Blattmann, P., Aebersold, R., Boutros, M. Tags: Cancer, Computational Biology, Genome-Scale & Integrative Biology Articles Source Type: research
