Genomic and bioinformatics tools to understand the biology of signal transducers and activators of transcription

2012 ◽  
Vol 10 (1) ◽  
Author(s):  
Keunsoo Kang ◽  
Lothar Hennighausen
Keyword(s):  
Regulatory Networks ◽  
Cell Types ◽  
Regulatory Sequences ◽  
Data Sets ◽  
Signal Transducers ◽  
Genome Wide ◽  
Bona Fide ◽  
Biochemical Signals ◽  
Different Cell Types

AbstractThe signal transducer and activator of transcription (STAT) family is activated by cytokines and conveys biochemical signals to the genome through binding to specific regulatory sequences, called IFN-γ-activated sequence (GAS) motifs. As common GAS motifs (TTCnnnGAA) contain only six conserved nucleotides, the mammalian genome harbors hundreds of thousands of copies of this sequence. However, it is not possible to predict which specific GAS motifs bind to STATs and are of functional significance. Here, we apply several layers of statistical, bioinformatics and experimental analyses to narrow down the number of GAS sites that might be of biological relevance. In particular, we determined the number of bona fide GAS motifs by utilizing publically available genome-wide STAT5 ChIP-seq data sets. Less than 10% of GAS motifs within the mouse genome are recognized by STAT5 in vivo and only a small portion of them are shared across different cell types. However, even bona fide STAT5 binding did not predict that the respective gene was under cytokine-STAT control. Therefore, additional bioinformatics, genomic and epigenetic parameters, such as patterns of histone modifications, are required to more reliably predict the behavior of cytokine-STAT regulatory networks.

scholarly journals Identifying regulatory and spatial genomic architectural elements using cell type independent machine and deep learning models

2020 ◽  
Author(s):  
Laura D. Martens ◽  
Oisín Faust ◽  
Liviu Pirvan ◽  
Dóra Bihary ◽  
Shamith A. Samarajiwa
Keyword(s):  
Deep Learning ◽  
Cell Types ◽  
Data Sets ◽  
Chromosome Conformation ◽  
Architectural Elements ◽  
Chromatin Interactions ◽  
Genome Wide ◽  
Chromatin Organisation ◽  
Different Cell Types

AbstractChromosome conformation capture methods such as Hi-C enables mapping of genome-wide chromatin interactions and is a promising technology to understand the role of spatial chromatin organisation in gene regulation. However, the generation and analysis of these data sets at high resolutions remain technically challenging and costly. We developed a machine and deep learning approach to predict functionally important, highly interacting chromatin regions (HICR) and topologically associated domain (TAD) boundaries independent of Hi-C data in both normal physiological states and pathological conditions such as cancer. This approach utilises gradient boosted trees and convolutional neural networks trained on both Hi-C and histone modification epigenomic data from three different cell types. Given only epigenomic modification data these models are able to predict chromatin interactions and TAD boundaries with high accuracy. We demonstrate that our models are transferable across cell types, indicating that combinatorial histone mark signatures may be universal predictors for highly interacting chromatin regions and spatial chromatin architecture elements.

scholarly journals ZetaSuite, A Computational Method for Analyzing Multi-dimensional High-throughput Data, Reveals Genes with Opposite Roles in Cancer Dependency

2021 ◽  
Author(s):  
Yajing Hao ◽  
Changwei Shao ◽  
Guofeng Zhao ◽  
Xiang-Dong Fu
Keyword(s):  
High Throughput ◽  
Regulatory Networks ◽  
Cell Types ◽  
Computational Method ◽  
Two Dimensional ◽  
Experimental Conditions ◽  
Term Survival ◽  
High Throughput Data ◽  
Genome Wide ◽  
Different Cell Types

AbstractThe rapid advance of high-throughput technologies has enabled the generation of two-dimensional or even multi-dimensional high-throughput data, e.g., genome-wide siRNA screen (1st dimension) for multiple changes in gene expression (2nd dimension) in many different cell types or tissues or under different experimental conditions (3rd dimension). We show that the simple Z-based statistic and derivatives are no longer suitable for analyzing such data because of the accumulation of experimental noise and/or off-target effects. Here, we introduce ZetaSuite, a statistical package designed to score and rank hits from two-dimensional screens, construct regulatory networks based on response similarities, and eliminate off-targets. Applying this method to two large cancer dependency screen datasets, we identify not only genes critical for cell fitness, but also those required for constraining cell proliferation. Strikingly, most of those cancer constraining genes function in DNA replication/repair checkpoint, suggesting that cancer cells also need to protect their genomes for long-term survival.

scholarly journals Therapeutic Attributes of Endocannabinoid System against Neuro-Inflammatory Autoimmune Disorders

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3389
Author(s):  
Ishtiaq Ahmed ◽  
Saif Ur Rehman ◽  
Shiva Shahmohamadnejad ◽  
Muhammad Anjum Zia ◽  
Muhammad Ahmad ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
Cell Types ◽  
Autoimmune Disorders ◽  
Specific Receptors ◽  
Different Cell Types

In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite. The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion. The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers. The therapeutic potential of cannabinoids for cancer—both in vivo and in vitro clinical trials—has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers. In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.

scholarly journals Profiling Bioactivity of the ToxCast Chemical Library Using BioMAP Primary Human Cell Systems

2009 ◽  
Vol 14 (9) ◽  
pp. 1054-1066 ◽  
Author(s):  
Keith A. Houck ◽  
David J. Dix ◽  
Richard S. Judson ◽  
Robert J. Kavlock ◽  
Jian Yang ◽  
...  
Keyword(s):  
Human Cell ◽  
Regulatory Networks ◽  
Cell Types ◽  
Environmental Chemicals ◽  
Data Sets ◽  
Chemical Library ◽  
Data Set ◽  
Cell Systems ◽  
Disease Biology ◽  
Nfκb Pathway

The complexity of human biology has made prediction of health effects as a consequence of exposure to environmental chemicals especially challenging. Complex cell systems, such as the Biologically Multiplexed Activity Profiling (BioMAP) primary, human, cell-based disease models, leverage cellular regulatory networks to detect and distinguish chemicals with a broad range of target mechanisms and biological processes relevant to human toxicity. Here the authors use the BioMAP human cell systems to characterize effects relevant to human tissue and inflammatory disease biology following exposure to the 320 environmental chemicals in the Environmental Protection Agency’s (EPA’s) ToxCast phase I library. The ToxCast chemicals were assayed at 4 concentrations in 8 BioMAP cell systems, with a total of 87 assay endpoints resulting in more than 100,000 data points. Within the context of the BioMAP database, ToxCast compounds could be classified based on their ability to cause overt cytotoxicity in primary human cell types or according to toxicity mechanism class derived from comparisons to activity profiles of BioMAP reference compounds. ToxCast chemicals with similarity to inducers of mitochondrial dysfunction, cAMP elevators, inhibitors of tubulin function, inducers of endoplasmic reticulum stress, or NFκB pathway inhibitors were identified based on this BioMAP analysis. This data set is being combined with additional ToxCast data sets for development of predictive toxicity models at the EPA. ( Journal of Biomolecular Screening 2009:1054-1066)

scholarly journals Bromodomain protein inhibition: a novel therapeutic strategy in rheumatic diseases

RMD Open ◽  
2018 ◽  
Vol 4 (2) ◽  
pp. e000744 ◽  
Author(s):  
Kerstin Klein
Keyword(s):  
Animal Models ◽  
Rheumatic Diseases ◽  
Transcriptional Activation ◽  
Therapeutic Strategy ◽  
Cell Types ◽  
Protein Inhibition ◽  
Different Cell Types ◽  
Novel Therapeutic

The reading of acetylation marks on histones by bromodomain (BRD) proteins is a key event in transcriptional activation. Small molecule inhibitors targeting bromodomain and extra-terminal (BET) proteins compete for binding to acetylated histones. They have strong anti-inflammatory properties and exhibit encouraging effects in different cell types in vitro and in animal models resembling rheumatic diseases in vivo. Furthermore, recent studies that focus on BRD proteins beyond BET family members are discussed.

scholarly journals Filopodyan: An open-source pipeline for the analysis of filopodia

2017 ◽  
Vol 216 (10) ◽  
pp. 3405-3422 ◽  
Author(s):  
Vasja Urbančič ◽  
Richard Butler ◽  
Benjamin Richier ◽  
Manuel Peter ◽  
Julia Mason ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Dynamic Properties ◽  
Cell Types ◽  
Molecular Heterogeneity ◽  
Interactive Editing ◽  
Motile Cells ◽  
Different Cell Types ◽  
Neuronal Growth Cones

Filopodia have important sensory and mechanical roles in motile cells. The recruitment of actin regulators, such as ENA/VASP proteins, to sites of protrusion underlies diverse molecular mechanisms of filopodia formation and extension. We developed Filopodyan (filopodia dynamics analysis) in Fiji and R to measure fluorescence in filopodia and at their tips and bases concurrently with their morphological and dynamic properties. Filopodyan supports high-throughput phenotype characterization as well as detailed interactive editing of filopodia reconstructions through an intuitive graphical user interface. Our highly customizable pipeline is widely applicable, capable of detecting filopodia in four different cell types in vitro and in vivo. We use Filopodyan to quantify the recruitment of ENA and VASP preceding filopodia formation in neuronal growth cones, and uncover a molecular heterogeneity whereby different filopodia display markedly different responses to changes in the accumulation of ENA and VASP fluorescence in their tips over time.

scholarly journals From blastocyst to gastrula: gene regulatory networks of embryonic stem cells and early mouse embryogenesis

2014 ◽  
Vol 369 (1657) ◽  
pp. 20130542 ◽  
Author(s):  
David-Emlyn Parfitt ◽  
Michael M. Shen
Keyword(s):  
Stem Cells ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Network Models ◽  
Cell Types ◽  
Mammalian Development ◽  
A Genome

To date, many regulatory genes and signalling events coordinating mammalian development from blastocyst to gastrulation stages have been identified by mutational analyses and reverse-genetic approaches, typically on a gene-by-gene basis. More recent studies have applied bioinformatic approaches to generate regulatory network models of gene interactions on a genome-wide scale. Such models have provided insights into the gene networks regulating pluripotency in embryonic and epiblast stem cells, as well as cell-lineage determination in vivo . Here, we review how regulatory networks constructed for different stem cell types relate to corresponding networks in vivo and provide insights into understanding the molecular regulation of the blastocyst–gastrula transition.

Abstract 1: Chemical Biology of Cardiac Regeleration: an Instructive Hydrogel-based Platform for Heart Repair

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Jay W Schneider ◽  
Sean C Goetsch ◽  
Serge Kyrychenko ◽  
Arturo Vegas ◽  
Daniel G Anderson ◽  
...  
Keyword(s):  
Ventricular Remodeling ◽  
Biological Response ◽  
Cell Types ◽  
Repair Process ◽  
Cardiomyocyte Hypertrophy ◽  
Heart Repair ◽  
Extracellular Matrix Molecules ◽  
Myocardial Biology ◽  
Biochemical Signals ◽  
Different Cell Types

Regeleration is the myocardium’s natural adaptive remodeling response to implanted biopolymer hydrogels, a new heart failure treatment modality with promising success in early clinical trials. Classified as a medical device capable of long-term myocardial engraftment, implanted hydrogels of varying molecular composition provide mechanical bulking and scaffolding support that can stabilize or reverse adverse ventricular remodeling. Additionally, natural or synthetically designed hydrogels encoding specific bioactivities or signaling functions can directly regulate myocardial biology to mediate heart repair. To gain mechanistic insight into the molecular and cellular biology and biochemistry of the biopolymer-myocardial interface, we studied two clinically relevant hydrogels - seaweed-derived alginate (Alg) and myomatrix (MMx), extracellular matrix molecules prepared from decellularized pig heart - in a mouse model. Alg and MMx differentially activated signal transduction cascades, recruited different cell types and produced distinctive gene expression signatures and patterns of cardiomyocyte hypertrophy, including muscle enhancer factor-2 (MEF2) and fetal gene program (re)activation. Chemically modifying Alg’s backbone structure correspondingly altered myocardium’s biological response, demonstrating the synthetic tunability of this repair process. These observations demonstrate that implanted biopolymer hydrogels drive unexpectedly robust and versatile regelerative responses in myocardium, transducing physical and biochemical signals to the cardiac genome that contribute to hydrogel function, providing a potential therapeutic target for enhancing hydrogel-mediated heart repair without stem cells.

scholarly journals Internalization mechanisms of cell-penetrating peptides

2020 ◽  
Vol 11 ◽  
pp. 101-123 ◽  
Author(s):  
Ivana Ruseska ◽  
Andreas Zimmer
Keyword(s):  
Cellular Uptake ◽  
Cell Types ◽  
Cell Penetrating Peptides ◽  
Uptake Mechanism ◽  
Black And White ◽  
Cell Penetrating ◽  
Basic Peptides ◽  
Different Cell Types ◽  
Immense Potential

In today’s modern era of medicine, macromolecular compounds such as proteins, peptides and nucleic acids are dethroning small molecules as leading therapeutics. Given their immense potential, they are highly sought after. However, their application is limited mostly due to their poor in vivo stability, limited cellular uptake and insufficient target specificity. Cell-penetrating peptides (CPPs) represent a major breakthrough for the transport of macromolecules. They have been shown to successfully deliver proteins, peptides, siRNAs and pDNA in different cell types. In general, CPPs are basic peptides with a positive charge at physiological pH. They are able to translocate membranes and gain entry to the cell interior. Nevertheless, the mechanism they use to enter cells still remains an unsolved piece of the puzzle. Endocytosis and direct penetration have been suggested as the two major mechanisms used for internalization, however, it is not all black and white in the nanoworld. Studies have shown that several CPPs are able to induce and shift between different uptake mechanisms depending on their concentration, cargo or the cell line used. This review will focus on the major internalization pathways CPPs exploit, their characteristics and regulation, as well as some of the factors that influence the cellular uptake mechanism.

scholarly journals Macropinocytosis in Different Cell Types: Similarities and Differences

Membranes ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 177 ◽  
Author(s):  
Xiao Peng Lin ◽  
Justine D. Mintern ◽  
Paul A. Gleeson
Keyword(s):  
Plasma Proteins ◽  
Physiological Function ◽  
Extracellular Fluid ◽  
Cell Types ◽  
Nutrient Sensing ◽  
Physiological Processes ◽  
Similarities And Differences ◽  
Endocytic Vesicles ◽  
Different Cell Types

Macropinocytosis is a unique pathway of endocytosis characterised by the nonspecific internalisation of large amounts of extracellular fluid, solutes and membrane in large endocytic vesicles known as macropinosomes. Macropinocytosis is important in a range of physiological processes, including antigen presentation, nutrient sensing, recycling of plasma proteins, migration and signalling. It has become apparent in recent years from the study of specialised cells that there are multiple pathways of macropinocytosis utilised by different cell types, and some of these pathways are triggered by different stimuli. Understanding the physiological function of macropinocytosis requires knowledge of the regulation and fate of the macropinocytosis pathways in a range of cell types. Here, we compare the mechanisms of macropinocytosis in different primary and immortalised cells, identify the gaps in knowledge in the field and discuss the potential approaches to analyse the function of macropinocytosis in vivo.

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