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Molecular Systems Biology

David Ochoa, Mindaugas Jonikas, Robert T Lawrence, Bachir El Debs, Joel Selkrig, Athanasios Typas, Judit Villén, Silvia Dm Santos, Pedro Beltrao
The coordinated regulation of protein kinases is a rapid mechanism that integrates diverse cues and swiftly determines appropriate cellular responses. However, our understanding of cellular decision-making has been limited by the small number of simultaneously monitored phospho-regulatory events. Here, we have estimated changes in activity in 215 human kinases in 399 conditions derived from a large compilation of phosphopeptide quantifications. This atlas identifies commonly regulated kinases as those that are central in the signaling network and defines the logic relationships between kinase pairs...
December 1, 2016: Molecular Systems Biology
Sören Müller, Siyuan John Liu, Elizabeth Di Lullo, Martina Malatesta, Alex A Pollen, Tomasz J Nowakowski, Gary Kohanbash, Manish Aghi, Arnold R Kriegstein, Daniel A Lim, Aaron Diaz
Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptors are frequently amplified and/or possess gain-of-function mutations in GBM However, clinical trials of tyrosine-kinase inhibitors have shown disappointing efficacy, in part due to intra-tumor heterogeneity. To assess the effect of clonal heterogeneity on gene expression, we derived an approach to map single-cell expression profiles to sequentially acquired mutations identified from exome sequencing...
November 25, 2016: Molecular Systems Biology
Dalila Bensaddek, Angus I Lamond
No abstract text is available yet for this article.
November 10, 2016: Molecular Systems Biology
Omer Karin, Avital Swisa, Benjamin Glaser, Yuval Dor, Uri Alon
Biological systems can maintain constant steady-state output despite variation in biochemical parameters, a property known as exact adaptation. Exact adaptation is achieved using integral feedback, an engineering strategy that ensures that the output of a system robustly tracks its desired value. However, it is unclear how physiological circuits also keep their output dynamics precise-including the amplitude and response time to a changing input. Such robustness is crucial for endocrine and neuronal homeostatic circuits because they need to provide a precise dynamic response in the face of wide variation in the physiological parameters of their target tissues; how such circuits compensate their dynamics for unavoidable natural fluctuations in parameters is unknown...
November 8, 2016: Molecular Systems Biology
Juan I Fuxman Bass, Carles Pons, Lucie Kozlowski, John S Reece-Hoyes, Shaleen Shrestha, Amy D Holdorf, Akihiro Mori, Chad L Myers, Albertha Jm Walhout
Transcription factors (TFs) play a central role in controlling spatiotemporal gene expression and the response to environmental cues. A comprehensive understanding of gene regulation requires integrating physical protein-DNA interactions (PDIs) with TF regulatory activity, expression patterns, and phenotypic data. Although great progress has been made in mapping PDIs using chromatin immunoprecipitation, these studies have only characterized ~10% of TFs in any metazoan species. The nematode C. elegans has been widely used to study gene regulation due to its compact genome with short regulatory sequences...
October 24, 2016: Molecular Systems Biology
Alan J Simmons, Amrita Banerjee, Eliot T McKinley, Cherie' R Scurrah, Charles A Herring, Leslie S Gewin, Ryota Masuzaki, Seth J Karp, Jeffrey L Franklin, Michael J Gerdes, Jonathan M Irish, Robert J Coffey, Ken S Lau
No abstract text is available yet for this article.
August 29, 2016: Molecular Systems Biology
Daniel A Charlebois, Gábor Balázsi
No abstract text is available yet for this article.
August 3, 2016: Molecular Systems Biology
David Healey, Kevin Axelrod, Jeff Gore
Genetically identical cells in microbial populations often exhibit a remarkable degree of phenotypic heterogeneity even in homogenous environments. Such heterogeneity is commonly thought to represent a bet-hedging strategy against environmental uncertainty. However, evolutionary game theory predicts that phenotypic heterogeneity may also be a response to negative frequency-dependent interactions that favor rare phenotypes over common ones. Here we provide experimental evidence for this alternative explanation in the context of the well-studied yeast GAL network...
August 3, 2016: Molecular Systems Biology
Bianca V Gapp, Tomasz Konopka, Thomas Penz, Vineet Dalal, Tilmann Bürckstümmer, Christoph Bock, Sebastian Mb Nijman
Reverse genetic screens have driven gene annotation and target discovery in model organisms. However, many disease-relevant genotypes and phenotypes cannot be studied in lower organisms. It is therefore essential to overcome technical hurdles associated with large-scale reverse genetics in human cells. Here, we establish a reverse genetic approach based on highly robust and sensitive multiplexed RNA sequencing of mutant human cells. We conduct 10 parallel screens using a collection of engineered haploid isogenic cell lines with knockouts covering tyrosine kinases and identify known and unexpected effects on signaling pathways...
August 1, 2016: Molecular Systems Biology
Christof Angermueller, Tanel Pärnamaa, Leopold Parts, Oliver Stegle
Technological advances in genomics and imaging have led to an explosion of molecular and cellular profiling data from large numbers of samples. This rapid increase in biological data dimension and acquisition rate is challenging conventional analysis strategies. Modern machine learning methods, such as deep learning, promise to leverage very large data sets for finding hidden structure within them, and for making accurate predictions. In this review, we discuss applications of this new breed of analysis approaches in regulatory genomics and cellular imaging...
July 29, 2016: Molecular Systems Biology
Guillaume Voisinne, Antonio García-Blesa, Karima Chaoui, Frédéric Fiore, Elise Bergot, Laura Girard, Marie Malissen, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Bernard Malissen, Romain Roncagalli
T-cell receptor (TCR) signaling is essential for the function of T cells and negatively regulated by the E3 ubiquitin-protein ligases CBL and CBLB Here, we combined mouse genetics and affinity purification coupled to quantitative mass spectrometry to monitor the dynamics of the CBL and CBLB signaling complexes that assemble in normal T cells over 600 seconds of TCR stimulation. We identify most previously known CBL and CBLB interacting partners, as well as a majority of proteins that have not yet been implicated in those signaling complexes...
July 29, 2016: Molecular Systems Biology
Laura Milligan, Vân A Huynh-Thu, Clémentine Delan-Forino, Alex Tuck, Elisabeth Petfalski, Rodrigo Lombraña, Guido Sanguinetti, Grzegorz Kudla, David Tollervey
Reversible modification of the RNAPII C-terminal domain links transcription with RNA processing and surveillance activities. To better understand this, we mapped the location of RNAPII carrying the five types of CTD phosphorylation on the RNA transcript, providing strand-specific, nucleotide-resolution information, and we used a machine learning-based approach to define RNAPII states. This revealed enrichment of Ser5P, and depletion of Tyr1P, Ser2P, Thr4P, and Ser7P in the transcription start site (TSS) proximal ~150 nt of most genes, with depletion of all modifications close to the poly(A) site...
June 10, 2016: Molecular Systems Biology
Lars M Steinmetz, Allan Jones
No abstract text is available yet for this article.
April 2016: Molecular Systems Biology
Hyunryul Ryu, Minhwan Chung, Maciej Dobrzyński, Dirk Fey, Yannick Blum, Sung Sik Lee, Matthias Peter, Boris N Kholodenko, Noo Li Jeon, Olivier Pertz
No abstract text is available yet for this article.
April 2016: Molecular Systems Biology
Quan Zhong, Samuel J Pevzner, Tong Hao, Yang Wang, Roberto Mosca, Jörg Menche, Mikko Taipale, Murat Taşan, Changyu Fan, Xinping Yang, Patrick Haley, Ryan R Murray, Flora Mer, Fana Gebreab, Stanley Tam, Andrew MacWilliams, Amélie Dricot, Patrick Reichert, Balaji Santhanam, Lila Ghamsari, Michael A Calderwood, Thomas Rolland, Benoit Charloteaux, Susan Lindquist, Albert-László Barabási, David E Hill, Patrick Aloy, Michael E Cusick, Yu Xia, Frederick P Roth, Marc Vidal
In cellular systems, biophysical interactions between macromolecules underlie a complex web of functional interactions. How biophysical and functional networks are coordinated, whether all biophysical interactions correspond to functional interactions, and how such biophysical-versus-functional network coordination is shaped by evolutionary forces are all largely unanswered questions. Here, we investigate these questions using an "inter-interactome" approach. We systematically probed the yeast and human proteomes for interactions between proteins from these two species and functionally characterized the resulting inter-interactome network...
April 2016: Molecular Systems Biology
Jerome C Nwachukwu, Sathish Srinivasan, Yangfan Zheng, Song Wang, Jian Min, Chune Dong, Zongquan Liao, Jason Nowak, Nicholas J Wright, René Houtman, Kathryn E Carlson, Jatinder S Josan, Olivier Elemento, John A Katzenellenbogen, Hai-Bing Zhou, Kendall W Nettles
Some estrogen receptor-α (ERα)-targeted breast cancer therapies such as tamoxifen have tissue-selective or cell-specific activities, while others have similar activities in different cell types. To identify biophysical determinants of cell-specific signaling and breast cancer cell proliferation, we synthesized 241 ERα ligands based on 19 chemical scaffolds, and compared ligand response using quantitative bioassays for canonical ERα activities and X-ray crystallography. Ligands that regulate the dynamics and stability of the coactivator-binding site in the C-terminal ligand-binding domain, called activation function-2 (AF-2), showed similar activity profiles in different cell types...
April 2016: Molecular Systems Biology
Nozomu Yachie, Evangelia Petsalaki, Joseph C Mellor, Jochen Weile, Yves Jacob, Marta Verby, Sedide B Ozturk, Siyang Li, Atina G Cote, Roberto Mosca, Jennifer J Knapp, Minjeong Ko, Analyn Yu, Marinella Gebbia, Nidhi Sahni, Song Yi, Tanya Tyagi, Dayag Sheykhkarimli, Jonathan F Roth, Cassandra Wong, Louai Musa, Jamie Snider, Yi-Chun Liu, Haiyuan Yu, Pascal Braun, Igor Stagljar, Tong Hao, Michael A Calderwood, Laurence Pelletier, Patrick Aloy, David E Hill, Marc Vidal, Frederick P Roth
High-throughput binary protein interaction mapping is continuing to extend our understanding of cellular function and disease mechanisms. However, we remain one or two orders of magnitude away from a complete interaction map for humans and other major model organisms. Completion will require screening at substantially larger scales with many complementary assays, requiring further efficiency gains in proteome-scale interaction mapping. Here, we report Barcode Fusion Genetics-Yeast Two-Hybrid (BFG-Y2H), by which a full matrix of protein pairs can be screened in a single multiplexed strain pool...
April 2016: Molecular Systems Biology
Mathias Uhlén, Björn M Hallström, Cecilia Lindskog, Adil Mardinoglu, Fredrik Pontén, Jens Nielsen
Quantifying the differential expression of genes in various human organs, tissues, and cell types is vital to understand human physiology and disease. Recently, several large-scale transcriptomics studies have analyzed the expression of protein-coding genes across tissues. These datasets provide a framework for defining the molecular constituents of the human body as well as for generating comprehensive lists of proteins expressed across tissues or in a tissue-restricted manner. Here, we review publicly available human transcriptome resources and discuss body-wide data from independent genome-wide transcriptome analyses of different tissues...
April 2016: Molecular Systems Biology
Tobias Bauer, Saskia Trump, Naveed Ishaque, Loreen Thürmann, Lei Gu, Mario Bauer, Matthias Bieg, Zuguang Gu, Dieter Weichenhan, Jan-Philipp Mallm, Stefan Röder, Gunda Herberth, Eiko Takada, Oliver Mücke, Marcus Winter, Kristin M Junge, Konrad Grützmann, Ulrike Rolle-Kampczyk, Qi Wang, Christian Lawerenz, Michael Borte, Tobias Polte, Matthias Schlesner, Michaela Schanne, Stefan Wiemann, Christina Geörg, Hendrik G Stunnenberg, Christoph Plass, Karsten Rippe, Junichiro Mizuguchi, Carl Herrmann, Roland Eils, Irina Lehmann
Epigenetic mechanisms have emerged as links between prenatal environmental exposure and disease risk later in life. Here, we studied epigenetic changes associated with maternal smoking at base pair resolution by mapping DNA methylation, histone modifications, and transcription in expectant mothers and their newborn children. We found extensive global differential methylation and carefully evaluated these changes to separate environment associated from genotype-related DNA methylation changes. Differential methylation is enriched in enhancer elements and targets in particular "commuting" enhancers having multiple, regulatory interactions with distal genes...
March 2016: Molecular Systems Biology
Stephen R Piccolo, Laura M Hoffman, Thomas Conner, Gajendra Shrestha, Adam L Cohen, Jeffrey R Marks, Leigh A Neumayer, Cori A Agarwal, Mary C Beckerle, Irene L Andrulis, Avrum E Spira, Philip J Moos, Saundra S Buys, William Evan Johnson, Andrea H Bild
The signaling events that drive familial breast cancer (FBC) risk remain poorly understood. While the majority of genomic studies have focused on genetic risk variants, known risk variants account for at most 30% of FBC cases. Considering that multiple genes may influence FBC risk, we hypothesized that a pathway-based strategy examining different data types from multiple tissues could elucidate the biological basis for FBC. In this study, we performed integrated analyses of gene expression and exome-sequencing data from peripheral blood mononuclear cells and showed that cell adhesion pathways are significantly and consistently dysregulated in women who develop FBC...
March 2016: Molecular Systems Biology
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