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Cell Systems

Lisa K Kutsche, Deisy M Gysi, Joerg Fallmann, Kerstin Lenk, Rebecca Petri, Anka Swiersy, Simon D Klapper, Karolina Pircs, Shahryar Khattak, Peter F Stadler, Johan Jakobsson, Katja Nowick, Volker Busskamp
Non-coding RNAs regulate many biological processes including neurogenesis. The brain-enriched miR-124 has been assigned as a key player of neuronal differentiation via its complex but little understood regulation of thousands of annotated targets. To systematically chart its regulatory functions, we used CRISPR/Cas9 gene editing to disrupt all six miR-124 alleles in human induced pluripotent stem cells. Upon neuronal induction, miR-124-deleted cells underwent neurogenesis and became functional neurons, albeit with altered morphology and neurotransmitter specification...
September 28, 2018: Cell Systems
Harold M McNamara, Stephanie Dodson, Yi-Lin Huang, Evan W Miller, Björn Sandstede, Adam E Cohen
Little is known about how individual cells sense the macroscopic geometry of their tissue environment. Here, we explore whether long-range electrical signaling can convey information on tissue geometry to individual cells. First, we studied an engineered electrically excitable cell line. Cells grown in patterned islands of different shapes showed remarkably diverse firing patterns under otherwise identical conditions, including regular spiking, period-doubling alternans, and arrhythmic firing. A Hodgkin-Huxley numerical model quantitatively reproduced these effects, showing how the macroscopic geometry affected the single-cell electrophysiology via the influence of gap junction-mediated electrical coupling...
September 27, 2018: Cell Systems
Rosa Martinez-Corral, Elba Raimundez, Yihan Lin, Michael B Elowitz, Jordi Garcia-Ojalvo
Many proteins exhibit dynamic activation patterns in the form of irregular pulses. Such behavior is typically attributed to a combination of positive and negative feedback loops in the underlying regulatory network. However, the presence of positive feedbacks is difficult to demonstrate unequivocally, raising the question of whether stochastic pulses can arise from negative feedback only. Here, we use the protein kinase A (PKA) system, a key regulator of the yeast pulsatile transcription factor Msn2, as a case example to show that irregular pulses of protein activity can arise from a negative feedback loop alone...
September 24, 2018: Cell Systems
Doruk Beyter, Miin S Lin, Yanbao Yu, Rembert Pieper, Vineet Bafna
Shotgun metaproteomics has the potential to reveal the functional landscape of microbial communities but lacks appropriate methods for complex samples with unknown compositions. In the absence of prior taxonomic information, tandem mass spectra would be searched against large pan-microbial databases, which requires heavy computational workload and reduces sensitivity. We present ProteoStorm, an efficient database search framework for large-scale metaproteomics studies, which identifies high-confidence peptide-spectrum matches (PSMs) while achieving a two-to-three orders-of-magnitude speedup over popular tools...
September 24, 2018: Cell Systems
Anil Korkut, Sobia Zaidi, Rupa S Kanchi, Shuyun Rao, Nancy R Gough, Andre Schultz, Xubin Li, Philip L Lorenzi, Ashton C Berger, Gordon Robertson, Lawrence N Kwong, Mike Datto, Jason Roszik, Shiyun Ling, Visweswaran Ravikumar, Ganiraju Manyam, Arvind Rao, Simon Shelley, Yuexin Liu, Zhenlin Ju, Donna Hansel, Guillermo de Velasco, Arjun Pennathur, Jesper B Andersen, Colm J O'Rourke, Kazufumi Ohshiro, Wilma Jogunoori, Bao-Ngoc Nguyen, Shulin Li, Hatice U Osmanbeyoglu, Jaffer A Ajani, Sendurai A Mani, Andres Houseman, Maciej Wiznerowicz, Jian Chen, Shoujun Gu, Wencai Ma, Jiexin Zhang, Pan Tong, Andrew D Cherniack, Chuxia Deng, Linda Resar, John N Weinstein, Lopa Mishra, Rehan Akbani
We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4)...
September 14, 2018: Cell Systems
Maike M K Hansen, Ravi V Desai, Michael L Simpson, Leor S Weinberger
Transcription is an episodic process characterized by probabilistic bursts, but how the transcriptional noise from these bursts is modulated by cellular physiology remains unclear. Using simulations and single-molecule RNA counting, we examined how cellular processes influence cell-to-cell variability (noise). The results show that RNA noise is higher in the cytoplasm than the nucleus in ∼85% of genes across diverse promoters, genomic loci, and cell types (human and mouse). Measurements show further amplification of RNA noise in the cytoplasm, fitting a model of biphasic mRNA conversion between translation- and degradation-competent states...
September 11, 2018: Cell Systems
Pau Creixell, Jai P Pandey, Antonio Palmeri, Moitrayee Bhattacharyya, Marc Creixell, Rama Ranganathan, David Pincus, Michael B Yaffe
The functional diversity of kinases enables specificity in cellular signal transduction. Yet how more than 500 members of the human kinome specifically receive regulatory inputs and convey information to appropriate substrates-all while using the common signaling output of phosphorylation-remains enigmatic. Here, we perform statistical co-evolution analysis, mutational scanning, and quantitative live-cell assays to reveal a hierarchical organization of the kinase domain that facilitates the orthogonal evolution of regulatory inputs and substrate outputs while maintaining catalytic function...
September 5, 2018: Cell Systems
Mingxun Wang, Jian Wang, Jeremy Carver, Benjamin S Pullman, Seong Won Cha, Nuno Bandeira
The increasing throughput and sharing of proteomics mass spectrometry data have now yielded over one-third of a million public mass spectrometry runs. However, these discoveries are not continuously aggregated in an open and error-controlled manner, which limits their utility. To facilitate the reusability of these data, we built the MassIVE Knowledge Base (MassIVE-KB), a community-wide, continuously updating knowledge base that aggregates proteomics mass spectrometry discoveries into an open reusable format with full provenance information for community scrutiny...
August 24, 2018: Cell Systems
John Selberg, Marcella Gomez, Marco Rolandi
The fields of synthetic biology, which focuses on genetic and cellular substrates, and bioelectronics, which focuses on interfacing electronics with biology, may appear to have little in common on the surface. However, we contend that there is potential for convergence between the two fields based on shared and complementary design principles from each field. We provide examples where this convergence is beginning to take place in the engineered measurement and control of cell populations, individual cells, and membrane transport...
September 26, 2018: Cell Systems
Davide Cacchiarelli, Xiaojie Qiu, Sanjay Srivatsan, Anna Manfredi, Michael Ziller, Eliah Overbey, Antonio Grimaldi, Jonna Grimsby, Prapti Pokharel, Kenneth J Livak, Shuqiang Li, Alexander Meissner, Tarjei S Mikkelsen, John L Rinn, Cole Trapnell
Cellular reprogramming through manipulation of defined factors holds great promise for large-scale production of cell types needed for use in therapy and for revealing principles of gene regulation. However, most reprogramming systems are inefficient, converting only a fraction of cells to the desired state. Here, we analyze MYOD-mediated reprogramming of human fibroblasts to myotubes, a well-characterized model system for direct conversion by defined factors, at pseudotemporal resolution using single-cell RNA-seq...
September 26, 2018: Cell Systems
Gregory L Medlock, Maureen A Carey, Dennis G McDuffie, Michael B Mundy, Natasa Giallourou, Jonathan R Swann, Glynis L Kolling, Jason A Papin
The diversity and number of species present within microbial communities create the potential for a multitude of interspecies metabolic interactions. Here, we develop, apply, and experimentally test a framework for inferring metabolic mechanisms associated with interspecies interactions. We perform pairwise growth and metabolome profiling of co-cultures of strains from a model mouse microbiota. We then apply our framework to dissect emergent metabolic behaviors that occur in co-culture. Based on one of the inferences from this framework, we identify and interrogate an amino acid cross-feeding interaction and validate that the proposed interaction leads to a growth benefit in vitro...
September 26, 2018: Cell Systems
Aleksej Zelezniak, Jakob Vowinckel, Floriana Capuano, Christoph B Messner, Vadim Demichev, Nicole Polowsky, Michael Mülleder, Stephan Kamrad, Bernd Klaus, Markus A Keller, Markus Ralser
A challenge in solving the genotype-to-phenotype relationship is to predict a cell's metabolome, believed to correlate poorly with gene expression. Using comparative quantitative proteomics, we found that differential protein expression in 97 Saccharomyces cerevisiae kinase deletion strains is non-redundant and dominated by abundance changes in metabolic enzymes. Associating differential enzyme expression landscapes to corresponding metabolomes using network models provided reasoning for poor proteome-metabolome correlations; differential protein expression redistributes flux control between many enzymes acting in concert, a mechanism not captured by one-to-one correlation statistics...
September 26, 2018: Cell Systems
Kathleen S Metz, Erika M Deoudes, Matthew E Berginski, Ivan Jimenez-Ruiz, Bulent Arman Aksoy, Jeff Hammerbacher, Shawn M Gomez, Douglas H Phanstiel
Protein kinases represent one of the largest gene families in eukaryotes and play roles in a wide range of cell signaling processes and human diseases. Current tools for visualizing kinase data in the context of the human kinome superfamily are limited to encoding data through the addition of nodes to a low-resolution image of the kinome tree. We present Coral, a user-friendly interactive web application for visualizing both quantitative and qualitative data. Unlike previous tools, Coral can encode data in three features (node color, node size, and branch color), allows three modes of kinome visualization (the traditional kinome tree as well as radial and dynamic force networks), and generates high-resolution scalable vector graphics files suitable for publication without the need for refinement using graphics editing software...
September 26, 2018: Cell Systems
Shawn French, Brittney E Coutts, Eric D Brown
Open-source electronics are becoming more prevalent in biological sciences, enabling novel and unique means of data acquisition. Here, we present 3D-printed, open-source tools to acquire fluorescence phenotypes with high temporal resolution. Printed fluorescence imaging boxes (PFIboxes) cost approximately 200 US dollars to assemble, can be placed in incubators or hypoxic chambers, and accurately read high-density colony arrays of microorganisms. We demonstrate the utility of PFIboxes using a time course gene expression approach, examining global Escherichia coli promoter activity using a fluorescent reporter library across a diverse panel of 15 antibiotics, each at several concentrations...
September 26, 2018: Cell Systems
Nils Eling, Arianne C Richard, Sylvia Richardson, John C Marioni, Catalina A Vallejos
Cell-to-cell transcriptional variability in otherwise homogeneous cell populations plays an important role in tissue function and development. Single-cell RNA sequencing can characterize this variability in a transcriptome-wide manner. However, technical variation and the confounding between variability and mean expression estimates hinder meaningful comparison of expression variability between cell populations. To address this problem, we introduce an analysis approach that extends the BASiCS statistical framework to derive a residual measure of variability that is not confounded by mean expression...
September 26, 2018: Cell Systems
Angel Stanoev, Amit Mhamane, Klaus C Schuermann, Hernán E Grecco, Wayne Stallaert, Martin Baumdick, Yannick Brüggemann, Maitreyi S Joshi, Pedro Roda-Navarro, Sven Fengler, Rabea Stockert, Lisaweta Roßmannek, Jutta Luig, Aneta Koseska, Philippe I H Bastiaens
The proto-oncogenic epidermal growth factor receptor (EGFR) is a tyrosine kinase whose sensitivity to growth factors and signal duration determines cellular behavior. We resolve how EGFR's response to epidermal growth factor (EGF) originates from dynamically established recursive interactions with spatially organized protein tyrosine phosphatases (PTPs). Reciprocal genetic PTP perturbations enabled identification of receptor-like PTPRG/J at the plasma membrane and ER-associated PTPN2 as the major EGFR dephosphorylating activities...
September 26, 2018: Cell Systems
H Efsun Arda, Jennifer Tsai, Yenny R Rosli, Paul Giresi, Rita Bottino, William J Greenleaf, Howard Y Chang, Seung K Kim
Understanding the genomic logic that underlies cellular diversity and developmental potential in the human pancreas will accelerate the growth of cell replacement therapies and reveal genetic risk mechanisms in diabetes. Here, we identified and characterized thousands of chromatin regions governing cell-specific gene regulation in human pancreatic endocrine and exocrine lineages, including islet β cells, α cells, duct, and acinar cells. Our findings have captured cellular ontogenies at the chromatin level, identified lineage-specific regulators potentially acting on these sites, and uncovered hallmarks of regulatory plasticity between cell types that suggest mechanisms to regenerate β cells from pancreatic endocrine or exocrine cells...
September 26, 2018: Cell Systems
Kristin L Patrick, Jason A Wojcechowskyj, Samantha L Bell, Morgan N Riba, Tao Jing, Sara Talmage, Pengbiao Xu, Ana L Cabello, Jiewei Xu, Michael Shales, David Jimenez-Morales, Thomas A Ficht, Paul de Figueiredo, James E Samuel, Pingwei Li, Nevan J Krogan, Robert O Watson
Intracellular bacterial pathogens secrete a repertoire of effector proteins into host cells that are required to hijack cellular pathways and cause disease. Despite decades of research, the molecular functions of most bacterial effectors remain unclear. To address this gap, we generated quantitative genetic interaction profiles between 36 validated and putative effectors from three evolutionarily divergent human bacterial pathogens and 4,190 yeast deletion strains. Correlating effector-generated profiles with those of yeast mutants, we recapitulated known biology for several effectors with remarkable specificity and predicted previously unknown functions for others...
September 26, 2018: Cell Systems
Ivan Junier, E Besray Unal, Eva Yus, Verónica Lloréns-Rico, Luis Serrano
No abstract text is available yet for this article.
August 22, 2018: Cell Systems
Ariya Shajii, Ibrahim Numanagić, Christopher Whelan, Bonnie Berger
Sequencing technologies are capturing longer-range genomic information at lower error rates, enabling alignment to genomic regions that are inaccessible with short reads. However, many methods are unable to align reads to much of the genome, recognized as important in disease, and thus report erroneous results in downstream analyses. We introduce EMA, a novel two-tiered statistical binning model for barcoded read alignment, that first probabilistically maps reads to potentially multiple "read clouds" and then within clouds by newly exploiting the non-uniform read densities characteristic of barcoded read sequencing...
August 22, 2018: Cell Systems
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