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Cell Systems

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https://www.readbyqxmd.com/read/28065574/a-blueprint-for-a-synthetic-genetic-feedback-controller-to-reprogram-cell-fate
#1
Domitilla Del Vecchio, Hussein Abdallah, Yili Qian, James J Collins
To artificially reprogram cell fate, experimentalists manipulate the gene regulatory networks (GRNs) that maintain a cell's phenotype. In practice, reprogramming is often performed by constant overexpression of specific transcription factors (TFs). This process can be unreliable and inefficient. Here, we address this problem by introducing a new approach to reprogramming based on mathematical analysis. We demonstrate that reprogramming GRNs using constant overexpression may not succeed in general. Instead, we propose an alternative reprogramming strategy: a synthetic genetic feedback controller that dynamically steers the concentration of a GRN's key TFs to any desired value...
January 3, 2017: Cell Systems
https://www.readbyqxmd.com/read/28065575/multiparametric-analysis-of-cell-shape-demonstrates-that-%C3%AE-pix-directly-couples-yap-activation-to-extracellular-matrix-adhesion
#2
Julia E Sero, Chris Bakal
Mechanical signals from the extracellular matrix (ECM) and cellular geometry regulate the nuclear translocation of transcriptional regulators such as Yes-associated protein (YAP). Elucidating how physical signals control the activity of mechanosensitive proteins poses a technical challenge, because perturbations that affect cell shape may also affect protein localization indirectly. Here, we present an approach that mitigates confounding effects of cell-shape changes, allowing us to identify direct regulators of YAP localization...
January 2, 2017: Cell Systems
https://www.readbyqxmd.com/read/28041762/combinatorial-gene-regulation-through-kinetic-control-of-the-transcription-cycle
#3
Clarissa Scholes, Angela H DePace, Álvaro Sánchez
Cells decide when, where, and to what level to express their genes by "computing" information from transcription factors (TFs) binding to regulatory DNA. How is the information contained in multiple TF-binding sites integrated to dictate the rate of transcription? The dominant conceptual and quantitative model is that TFs combinatorially recruit one another and RNA polymerase to the promoter by direct physical interactions. Here, we develop a quantitative framework to explore kinetic control, an alternative model in which combinatorial gene regulation can result from TFs working on different kinetic steps of the transcription cycle...
December 26, 2016: Cell Systems
https://www.readbyqxmd.com/read/28017544/context-specificity-in-causal-signaling-networks-revealed-by-phosphoprotein-profiling
#4
Steven M Hill, Nicole K Nesser, Katie Johnson-Camacho, Mara Jeffress, Aimee Johnson, Chris Boniface, Simon E F Spencer, Yiling Lu, Laura M Heiser, Yancey Lawrence, Nupur T Pande, James E Korkola, Joe W Gray, Gordon B Mills, Sach Mukherjee, Paul T Spellman
Signaling networks downstream of receptor tyrosine kinases are among the most extensively studied biological networks, but new approaches are needed to elucidate causal relationships between network components and understand how such relationships are influenced by biological context and disease. Here, we investigate the context specificity of signaling networks within a causal conceptual framework using reverse-phase protein array time-course assays and network analysis approaches. We focus on a well-defined set of signaling proteins profiled under inhibition with five kinase inhibitors in 32 contexts: four breast cancer cell lines (MCF7, UACC812, BT20, and BT549) under eight stimulus conditions...
December 19, 2016: Cell Systems
https://www.readbyqxmd.com/read/27989508/a-multi-network-approach-identifies-protein-specific-co-expression-in-asymptomatic-and-symptomatic-alzheimer-s-disease
#5
Nicholas T Seyfried, Eric B Dammer, Vivek Swarup, Divya Nandakumar, Duc M Duong, Luming Yin, Qiudong Deng, Tram Nguyen, Chadwick M Hales, Thomas Wingo, Jonathan Glass, Marla Gearing, Madhav Thambisetty, Juan C Troncoso, Daniel H Geschwind, James J Lah, Allan I Levey
Here, we report proteomic analyses of 129 human cortical tissues to define changes associated with the asymptomatic and symptomatic stages of Alzheimer's disease (AD). Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD phenotypes. A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in the asymptomatic stages. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation...
December 14, 2016: Cell Systems
https://www.readbyqxmd.com/read/27916600/mapping-complex-traits-in-a-diversity-outbred-f1-mouse-population-identifies-germline-modifiers-of-metastasis-in-human-prostate-cancer
#6
Jean M Winter, Derek E Gildea, Jonathan P Andreas, Daniel M Gatti, Kendra A Williams, Minnkyong Lee, Ying Hu, Suiyuan Zhang, James C Mullikin, Tyra G Wolfsberg, Shannon K McDonnell, Zachary C Fogarty, Melissa C Larson, Amy J French, Daniel J Schaid, Stephen N Thibodeau, Gary A Churchill, Nigel P S Crawford
It is unclear how standing genetic variation affects the prognosis of prostate cancer patients. To provide one controlled answer to this problem, we crossed a dominant, penetrant mouse model of prostate cancer to Diversity Outbred mice, a collection of animals that carries over 40 million SNPs. Integration of disease phenotype and SNP variation data in 493 F1 males identified a metastasis modifier locus on Chromosome 8 (LOD = 8.42); further analysis identified the genes Rwdd4, Cenpu, and Casp3 as functional effectors of this locus...
November 25, 2016: Cell Systems
https://www.readbyqxmd.com/read/27866946/systems-genetics-approach-identifies-gene-pathways-and-adamts2-as-drivers-of-isoproterenol-induced-cardiac-hypertrophy-and-cardiomyopathy-in-mice
#7
Christoph D Rau, Milagros C Romay, Mary Tuteryan, Jessica J-C Wang, Marc Santolini, Shuxun Ren, Alain Karma, James N Weiss, Yibin Wang, Aldons J Lusis
We previously reported a genetic analysis of heart failure traits in a population of inbred mouse strains treated with isoproterenol to mimic catecholamine-driven cardiac hypertrophy. Here, we apply a co-expression network algorithm, wMICA, to perform a systems-level analysis of left ventricular transcriptomes from these mice. We describe the features of the overall network but focus on a module identified in treated hearts that is strongly related to cardiac hypertrophy and pathological remodeling. Using the causal modeling algorithm NEO, we identified the gene Adamts2 as a putative regulator of this module and validated the predictive value of NEO using small interfering RNA-mediated knockdown in neonatal rat ventricular myocytes...
November 16, 2016: Cell Systems
https://www.readbyqxmd.com/read/27866947/integrating-gwas-and-co-expression-network-data-identifies-bone-mineral-density-genes-sptbn1-and-mark3-and-an-osteoblast-functional-module
#8
Gina M Calabrese, Larry D Mesner, Joseph P Stains, Steven M Tommasini, Mark C Horowitz, Clifford J Rosen, Charles R Farber
Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. Genome-wide association studies (GWAS) for BMD have identified dozens of associations; yet, the genes responsible for most associations remain elusive. Here, we used a bone co-expression network to predict causal genes at BMD GWAS loci based on the premise that genes underlying a disease are often functionally related and functionally related genes are often co-expressed. By mapping genes implicated by BMD GWAS onto a bone co-expression network, we predicted and inferred the function of causal genes for 30 of 64 GWAS loci...
November 15, 2016: Cell Systems
https://www.readbyqxmd.com/read/28009266/elucidation-of-signaling-pathways-from-large-scale-phosphoproteomic-data-using-protein-interaction-networks
#9
Jan Daniel Rudolph, Marjo de Graauw, Bob van de Water, Tamar Geiger, Roded Sharan
Phosphoproteomic experiments typically identify sites within a protein that are differentially phosphorylated between two or more cell states. However, the interpretation of these data is hampered by the lack of methods that can translate site-specific information into global maps of active proteins and signaling networks, especially as the phosphoproteome is often undersampled. Here, we describe PHOTON, a method for interpreting phosphorylation data within their signaling context, as captured by protein-protein interaction networks, to identify active proteins and pathways and pinpoint functional phosphosites...
December 21, 2016: Cell Systems
https://www.readbyqxmd.com/read/28009265/rna-structural-determinants-of-optimal-codons-revealed-by-mage-seq
#10
Eric D Kelsic, Hattie Chung, Niv Cohen, Jimin Park, Harris H Wang, Roy Kishony
Synonymous codon choices at the beginning of genes optimize 5' RNA structures for enhanced translation initiation, but less is known about mechanisms that drive codon optimization downstream within the gene. To understand what determines codon choices across a gene, we generated 12,726 in situ codon mutants in the Escherichia coli essential gene infA and measured their fitness by combining multiplex automated genome engineering mutagenesis with amplicon deep sequencing (MAGE-seq). Correlating predicted 5' RNA structure with fitness revealed that codons even far from the start of the gene are deleterious if they disrupt the native 5' RNA conformation...
December 21, 2016: Cell Systems
https://www.readbyqxmd.com/read/28009264/noise-induces-hopping-between-nf-%C3%AE%C2%BAb-entrainment-modes
#11
Mathias Heltberg, Ryan A Kellogg, Sandeep Krishna, Savaş Tay, Mogens H Jensen
Oscillations and noise drive many processes in biology, but how both affect the activity of the transcription factor nuclear factor κB (NF-κB) is not understood. Here, we observe that when NF-κB oscillations are entrained by periodic tumor necrosis factor (TNF) inputs in experiments, NF-κB exhibits jumps between frequency modes, a phenomenon we call "cellular mode-hopping." By comparing stochastic simulations of NF-κB oscillations to deterministic simulations conducted inside and outside the chaotic regime of parameter space, we show that noise facilitates mode-hopping in all regimes...
December 21, 2016: Cell Systems
https://www.readbyqxmd.com/read/28009263/the-evolution-of-the-algorithms-for-collective-behavior
#12
REVIEW
Deborah M Gordon
Collective behavior is the outcome of a network of local interactions. Here, I consider collective behavior as the result of algorithms that have evolved to operate in response to a particular environment and physiological context. I discuss how algorithms are shaped by the costs of operating under the constraints that the environment imposes, the extent to which the environment is stable, and the distribution, in space and time, of resources. I suggest that a focus on the dynamics of the environment may provide new hypotheses for elucidating the algorithms that produce the collective behavior of cellular systems...
December 21, 2016: Cell Systems
https://www.readbyqxmd.com/read/28009262/cell-lineage-trees-bear-fruit
#13
Jordi Garcia-Ojalvo
Two inference approaches harness the information present in cell lineage trees to better understand the dynamic transitions between cell states.
December 21, 2016: Cell Systems
https://www.readbyqxmd.com/read/28009261/turning-it-up-to-11-modular-proteins-amplify-rna-sensors-for-sophisticated-circuitry
#14
James Chappell, Julius B Lucks
Ligand-sensing RNA switches can be enhanced using protein-based amplifiers to deliver sophisticated signal-processing genetic circuitry.
December 21, 2016: Cell Systems
https://www.readbyqxmd.com/read/28009260/entraining-oscillations-in-the-nf-%C3%AE%C2%BAb-signaling-system-with-a-little-help-from-noise
#15
Marc Lefranc
Two studies show that noise is a key ingredient of new mechanisms for entraining the NF-κB system.
December 21, 2016: Cell Systems
https://www.readbyqxmd.com/read/28009259/principles-of-systems-biology-no-12
#16
(no author information available yet)
This month: Plants take center stage with fascinating insights into disease susceptibility and engineered pathways for photosynthesis. Also, a wearable stethoscope, new noncanonical miRNA targeting rules, Hsf1, and transcription.
December 21, 2016: Cell Systems
https://www.readbyqxmd.com/read/28009258/making-space-for-time
#17
EDITORIAL
H Craig Mak
No abstract text is available yet for this article.
December 21, 2016: Cell Systems
https://www.readbyqxmd.com/read/27889536/compact-integration-of-multi-network-topology-for-functional-analysis-of-genes
#18
Hyunghoon Cho, Bonnie Berger, Jian Peng
The topological landscape of molecular or functional interaction networks provides a rich source of information for inferring functional patterns of genes or proteins. However, a pressing yet-unsolved challenge is how to combine multiple heterogeneous networks, each having different connectivity patterns, to achieve more accurate inference. Here, we describe the Mashup framework for scalable and robust network integration. In Mashup, the diffusion in each network is first analyzed to characterize the topological context of each node...
December 21, 2016: Cell Systems
https://www.readbyqxmd.com/read/27840078/design-and-construction-of-generalizable-rna-protein-hybrid-controllers-by-level-matched-genetic-signal-amplification
#19
Yen-Hsiang Wang, Maureen McKeague, Tammy M Hsu, Christina D Smolke
For synthetic biology applications, protein-based transcriptional genetic controllers are limited in terms of orthogonality, modularity, and portability. Although ribozyme-based switches can address these issues, their current two-stage architectures and limited dynamic range hinder their broader incorporation into systems-level genetic controllers. Here, we address these challenges by implementing an RNA-protein hybrid controller with a three-stage architecture that introduces a transcription-based amplifier between an RNA sensor and a protein actuator...
December 21, 2016: Cell Systems
https://www.readbyqxmd.com/read/27818083/shotgun-metagenomics-of-250-adult-twins-reveals-genetic-and-environmental-impacts-on-the-gut-microbiome
#20
Hailiang Xie, Ruijin Guo, Huanzi Zhong, Qiang Feng, Zhou Lan, Bingcai Qin, Kirsten J Ward, Matthew A Jackson, Yan Xia, Xu Chen, Bing Chen, Huihua Xia, Changlu Xu, Fei Li, Xun Xu, Jumana Yousuf Al-Aama, Huanming Yang, Jian Wang, Karsten Kristiansen, Jun Wang, Claire J Steves, Jordana T Bell, Junhua Li, Timothy D Spector, Huijue Jia
The gut microbiota has been typically viewed as an environmental factor for human health. Twins are well suited for investigating the concordance of their gut microbiomes and decomposing genetic and environmental influences. However, existing twin studies utilizing metagenomic shotgun sequencing have included only a few samples. Here, we sequenced fecal samples from 250 adult twins in the TwinsUK registry and constructed a comprehensive gut microbial reference gene catalog. We demonstrate heritability of many microbial taxa and functional modules in the gut microbiome, including those associated with diseases...
December 21, 2016: Cell Systems
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