scholarly journals Uncovering the cell type specificity of blood sample derived gene signatures using RNA expression data

2019 ◽  
Author(s):  
Mikhail Pomaznoy ◽  
Brendan Ha ◽  
Bjoern Peters
Keyword(s):  
Blood Cell ◽  
Web Application ◽  
Cell Lineage ◽  
Complex Mixture ◽  
Cell Types ◽  
Cell Type Specificity ◽  
Signature Genes ◽  
Expression Of Genes ◽  
Biological Interpretation ◽  
Different Cell Types

AbstractAnalysis of transcriptomic data derived from blood samples is complicated by the complex mixture of cell types such samples contain. Transcriptomic signatures derived from such samples are often driven by a particular cell lineage within the mixture. Identifying this most contributing lineage can help to provide a biological interpretation of the signature. We created a web application CellTypeScore which quantifies and visually represents the expression level of signature genes in common blood cell types. This is done by constructing an interactive stacked bar plot with the bars representing expression of genes across blood cell types. Summed scores serve as a measure of how highly the combined signature is expressed in different cell types. An online version of the application can be found at https://tools.dice-database.org/celltypescore/.

scholarly journals A conserved expression signature predicts growth rate and reveals cell & lineage-specific differences

2019 ◽  
Author(s):  
Zhisheng Jiang ◽  
Serena Francesca Generoso ◽  
Marta Badia ◽  
Bernhard Payer ◽  
Lucas B. Carey
Keyword(s):  
Cell Lineage ◽  
Gene Expression Signature ◽  
Cell Types ◽  
Eukaryotic Cell ◽  
Rna Seq ◽  
Cell Type Specificity ◽  
Expression Signature ◽  
Differentiated Cells ◽  
Different Cell Types ◽  
High Degree

By performing RNA-seq on cells FACS sorted by their proliferation rate, this study identifies a gene expression signature capable of predicting proliferation rates in diverse eukaryotic cell types and species. This signature, applied to scRNAseq data from C.elegans, reveals lineage-specific differences in proliferation during development. In contrast to the universality of the proliferation signature, mitochondria and metabolism related genes show a high degree of cell-type specificity; mouse pluripotent stem cells (mESCs) and differentiated cells (fibroblasts) exhibit opposite relations between mitochondria state and proliferation. Furthermore, we identified a slow proliferating subpopulation of mESCs with higher expression of pluripotency genes. Finally, we show that fast and slow proliferating subpopulations are differentially sensitive to mitochondria inhibitory drugs in different cell types.

Leveraging the cell lineage to predict cell type specificity of regulatory variation from bulk genomics

Genetics ◽  
2021 ◽  
Author(s):  
Gal Yankovitz ◽  
Ofir Cohn ◽  
Eran Bacharach ◽  
Naama Peshes-Yaloz ◽  
Yael Steuerman ◽  
...  
Keyword(s):  
Cell Lineage ◽  
Cell Types ◽  
Genetic Effects ◽  
Transcriptome Data ◽  
Cell Type ◽  
Cell Type Specificity ◽  
Dynamic Changes ◽  
Lineage Tree ◽  
Different Cell Types ◽  
Heterogeneous Tissues

Abstract Recent computational methods have enabled the inference of the cell-type-specificity of eQTLs based on bulk transcriptomes from highly heterogeneous tissues. However, these methods are limited in their scalability to highly heterogeneous tissues and limited in their broad applicability to any cell-type specificity of eQTLs. Here we present and demonstrate Cell Lineage Genetics (CeL-Gen), a novel computational approach that allows inference of eQTLs together with the subsets of cell types in which they have an effect, from bulk transcriptome data. To obtain improved scalability and broader applicability, CeL-Gen takes as input the known cell lineage tree and relies on the observation that dynamic changes in genetic effects occur relatively infrequently during cell differentiation. CeL-Gen can therefore be used not only to tease apart genetic effects derived from different cell types but also to infer the particular differentiation steps in which genetic effects are altered.

scholarly journals Advantages of using graph databases to explore chromatin conformation capture experiments

2021 ◽  
Vol 22 (S2) ◽  
Author(s):  
Daniele D’Agostino ◽  
Pietro Liò ◽  
Marco Aldinucci ◽  
Ivan Merelli
Keyword(s):  
Web Application ◽  
High Throughput Sequencing ◽  
Cell Types ◽  
Graph Database ◽  
Graph Databases ◽  
Sources Of Information ◽  
Chromosome Conformation ◽  
Wide Scale ◽  
User Friendly ◽  
Different Cell Types

Abstract Background High-throughput sequencing Chromosome Conformation Capture (Hi-C) allows the study of DNA interactions and 3D chromosome folding at the genome-wide scale. Usually, these data are represented as matrices describing the binary contacts among the different chromosome regions. On the other hand, a graph-based representation can be advantageous to describe the complex topology achieved by the DNA in the nucleus of eukaryotic cells. Methods Here we discuss the use of a graph database for storing and analysing data achieved by performing Hi-C experiments. The main issue is the size of the produced data and, working with a graph-based representation, the consequent necessity of adequately managing a large number of edges (contacts) connecting nodes (genes), which represents the sources of information. For this, currently available graph visualisation tools and libraries fall short with Hi-C data. The use of graph databases, instead, supports both the analysis and the visualisation of the spatial pattern present in Hi-C data, in particular for comparing different experiments or for re-mapping omics data in a space-aware context efficiently. In particular, the possibility of describing graphs through statistical indicators and, even more, the capability of correlating them through statistical distributions allows highlighting similarities and differences among different Hi-C experiments, in different cell conditions or different cell types. Results These concepts have been implemented in NeoHiC, an open-source and user-friendly web application for the progressive visualisation and analysis of Hi-C networks based on the use of the Neo4j graph database (version 3.5). Conclusion With the accumulation of more experiments, the tool will provide invaluable support to compare neighbours of genes across experiments and conditions, helping in highlighting changes in functional domains and identifying new co-organised genomic compartments.

scholarly journals Computational approaches towards reducing contamination in single-cell RNA-seq data

2020 ◽  
Author(s):  
Siamak Yousefi ◽  
Hao Chen ◽  
Jesse F. Ingels ◽  
Melinda S. McCarty ◽  
Arthur G. Centeno ◽  
...  
Keyword(s):  
Single Cell ◽  
Single Cells ◽  
Real Life ◽  
Cell Types ◽  
Cell Capture ◽  
Rna Seq ◽  
Sequence Analyses ◽  
Cell Functions ◽  
Biological Interpretation ◽  
Different Cell Types

SUMMARYSingle cell RNA sequencing has enabled quantification of single cells and identification of different cell types and subtypes as well as cell functions in different tissues. Single cell RNA sequence analyses assume acquired RNAs correspond to cells, however, RNAs from contamination within the input data are also captured by these assays. The sequencing of background contamination as well as unwanted cells making their way to the final assay Potentially confound the correct biological interpretation of single cell transcriptomic data. Here we demonstrate two approaches to deal with background contamination as well as profiling of unwanted cells in the assays. We use three real-life datasets of whole-cell capture and nucleotide single-cell captures generated by Fluidigm and 10x technologies and show that these methods reduce the effect of contamination, strengthen clustering of cells and improves biological interpretation.

scholarly journals Novel cost-efficient protein-membrane based system for cells co-cultivation and modeling the intercellular communication

2021 ◽  
Author(s):  
Artem Minin ◽  
Igor Blatov ◽  
Valeria Lebedeva ◽  
Maxim Tuchai ◽  
Varvara Pozdina ◽  
...  
Keyword(s):  
Growth Factors ◽  
A549 Cells ◽  
Cell Types ◽  
Homogeneous Population ◽  
Paracrine Effects ◽  
Expression Of Genes ◽  
Custom Made ◽  
Cost Efficient ◽  
Different Cell Types

In vitro systems serve as compact and manipulate models to investigate interactions between different cell types. A homogeneous population of cells predictably and uniformly responds to external factors. In a heterogeneous cell population, the effect of external growth factors is perceived in the context of intercellular interactions. Indirect cell co-cultivation allows one to observe the paracrine effects of cells and separately analyze cell populations. The article describes an application of custom-made cell co-cultivation systems based on protein membranes separated from the bottom of the vessel by the 3d printed holder or kept afloat by a magnetic field. Using the proposed co-cultivation system, we analyzed the interaction of A549 cells and fibroblasts, in the presence and absence of growth factors. During co-cultivation of cells, the expression of genes of the activation for epithelial and mesenchymal transitions decreases. The article proposes the application of a newly available system for the co-cultivation of different cell types.

scholarly journals Massively parallel single cell lineage tracing using CRISPR/Cas9 induced genetic scars

2017 ◽  
Author(s):  
Bastiaan Spanjaard ◽  
Bo Hu ◽  
Nina Mitic ◽  
Jan Philipp Junker
Keyword(s):  
Single Cell ◽  
Computational Analysis ◽  
Systematic Approach ◽  
Single Cells ◽  
Cell Lineage ◽  
Transcriptome Profiling ◽  
Cell Types ◽  
Lineage Tracing ◽  
Lineage Trees ◽  
Different Cell Types

A key goal of developmental biology is to understand how a single cell transforms into a full-grown organism consisting of many different cell types. Single-cell RNA-sequencing (scRNA-seq) has become a widely-used method due to its ability to identify all cell types in a tissue or organ in a systematic manner 1–3. However, a major challenge is to organize the resulting taxonomy of cell types into lineage trees revealing the developmental origin of cells. Here, we present a strategy for simultaneous lineage tracing and transcriptome profiling in thousands of single cells. By combining scRNA-seq with computational analysis of lineage barcodes generated by genome editing of transgenic reporter genes, we reconstruct developmental lineage trees in zebrafish larvae and adult fish. In future analyses, LINNAEUS (LINeage tracing by Nuclease-Activated Editing of Ubiquitous Sequences) can be used as a systematic approach for identifying the lineage origin of novel cell types, or of known cell types under different conditions.

Immunological changes accompanying the development of experimental neoplastic process

2015 ◽  
Vol 6 (2) ◽  
pp. 96-108
Author(s):  
Elena Aleksandrovna Dementeva ◽  
Olga Petrovna Gurina
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Genome Stability ◽  
Cell Types ◽  
Transformation Process ◽  
The Body ◽  
Expression Of Genes ◽  
Neoplastic Process ◽  
And Control ◽  
Different Cell Types

The key immunology problem remains the understanding of the mechanisms for the effective protection of the body against various pathogens with simultaneous suppression of the immune response to autoantigens. The pathogenesis of neoplastic pathological processes includes violations of the mechanisms of normal cell growth and cell proliferation. Antitumor immune response is a complex event, involving many different cell types. But despite the ability of the immune system to recognize and respond to a variety of tumor-associated antigens, the neoplastic process overcomes the protective forces of the organism, grows and spreads. For cancer cells characterized by independence from antiproliferative signals, autocrine stimulation of growth disturbances in the system, induction of apoptosis and control of genome stability. As a result of accumulation of genetic and epigenetic changes in tumor cells differ significantly from the normal range and the level of expression of genes involved in the transformation process, the accumulation of mutations in key genes promoters and suppressors of tumorigenesis. This creates the opportunity for recognition by cells of the immune system. The study of changes in value and operation of the various elements of the immune system in the development of experimental neoplastic process allows you to identify the mechanisms of interaction in the system «malignant tumor-immune system, to assess patterns of interaction with other organs and tissues, to create a theoretical pathogenetically reasonable premise for the development of anticancer therapy.

scholarly journals Mutagenesis of human cytomegalovirus glycoprotein L disproportionately disrupts gH/gL/gO over gH/gL/pUL128-131.

2021 ◽  
Author(s):  
Eric P. Schultz ◽  
Qin Yu ◽  
Cora Stegmann ◽  
Le Zhang Day ◽  
Jean-Marc Lanchy ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Neutralizing Antibodies ◽  
Complex Mixture ◽  
Cell Types ◽  
Human Populations ◽  
Persistent Infections ◽  
Bac Clones ◽  
Dependent Cell ◽  
Different Cell Types ◽  
Significant Disease

Cell-free and cell-to-cell spread of herpesviruses involves a core fusion apparatus comprised of the fusion protein glycoprotein B (gB) and the regulatory factor gH/gL. The human cytomegalovirus (HCMV) gH/gL/gO and gH/gL/pUL128-131 facilitate spread in different cell types. The gO and pUL128-131 components bind distinct receptors, but the how the gH/gL portion of the complexes functionally compare is not understood. We previously characterized a panel of gL mutants by transient expression and showed that many were impaired for gH/gL-gB dependent cell-cell fusion, but were still able to form gH/gL/pUL128-131 and induce receptor-interference. Here, the gL mutants were engineered into the HCMV BAC clones TB40/e-BAC4 (TB), TR and Merlin (ME), which differ in their utilization of the two complexes for entry and spread. Several of the gL mutations disproportionately impacted gH/gL/gO-dependent entry and spread over gH/gL/pUL128-131 processes. Effects of some mutants could be explained by impaired gH/gL/gO assembly, but other mutants impacted gH/gL/gO function. Soluble gH/gL/gO containing the L201 mutant failed to block HCMV infection despite unimpaired binding to PDGFRα, indicating the existence of other important gH/gL/gO receptors. Another mutant (L139) enhanced the gH/gL/gO-dependent cell-free spread of TR, suggesting a “hyperactive” gH/gL/gO. Recently published crystallography and cryo-EM studies suggest structural conservation of the gH/gL underlying gH/gL/gO and gH/gL/pUL128-131. However, our data suggest important differences in the gH/gL of the two complexes and support a model in which gH/gL/gO can provide an activation signal for gB. IMPORTANCE The endemic beta -herpesvirus HCMV circulates in human populations as a complex mixture of genetically distinct variants, establishes lifelong persistent infections, and causes significant disease in neonates and immunocompromised adults. This study capitalizes on our recent characterizations of three genetically distinct HCMV BAC clones to discern the functions of the envelope glycoprotein complexes gH/gL/gO and gH/gL/pUL128-13, which are promising vaccine targets that share the herpesvirus core fusion apparatus component, gH/gL. Mutations in the shared gL subunit disproportionally affected gH/gL/gO, demonstrating mechanistic differences between the two complexes, and may provide a basis for more refined evaluations of neutralizing antibodies.

Cell–cell interactions during patterning of the Arabidopsis anther

2010 ◽  
Vol 38 (2) ◽  
pp. 571-576 ◽  
Author(s):  
Xiaoqi Feng ◽  
Hugh G. Dickinson
Keyword(s):  
Reproductive Development ◽  
Cell Types ◽  
Cell Lineages ◽  
Expression Of Genes ◽  
Accurate Picture ◽  
Model Plant Arabidopsis Thaliana ◽  
Key Steps ◽  
Different Cell Types ◽  
Experimental Strategies ◽  
Plant Arabidopsis Thaliana

Key steps in the evolution of the angiosperm anther include the patterning of the concentrically organized microsporangium and the incorporation of four such microsporangia into a leaf-like structure. Mutant studies in the model plant Arabidopsis thaliana are leading to an increasingly accurate picture of (i) the cell lineages culminating in the different cell types present in the microsporangium (the microsporocytes, the tapetum, and the middle and endothecial layers), and (ii) some of the genes responsible for specifying their fates. However, the processes that confer polarity on the developing anther and position the microsporangia within it remain unclear. Certainly, data from a range of experimental strategies suggest that hormones play a central role in establishing polarity and the patterning of the anther initial, and may be responsible for locating the microsporangia. But the fact that microsporangia were originally positioned externally suggests that their development is likely to be autonomous, perhaps with the reproductive cells generating signals controlling the growth and division of the investing anther epidermis. These possibilities are discussed in the context of the expression of genes which initiate and maintain male and female reproductive development, and in the perspective of our current views of anther evolution.

scholarly journals Cellular deconvolution of GTEx tissues powers eQTL studies to discover thousands of novel disease and cell-type associated regulatory variants

2019 ◽  
Author(s):  
Margaret K. R. Donovan ◽  
Agnieszka D’Antonio-Chronowska ◽  
Matteo D’Antonio ◽  
Kelly A. Frazer
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Expression Profiles ◽  
Malignant Neoplasm ◽  
Cell Types ◽  
Mouse Cell ◽  
Tissue Type ◽  
Cell Type ◽  
Signature Genes ◽  
Different Cell Types

AbstractThe Genotype-Tissue Expression (GTEx) resource has contributed a wealth of novel insights into the regulatory impact of genetic variation on gene expression across human tissues, however thus far has not been utilized to study how variation acts at the resolution of the different cell types composing the tissues. To address this gap, using liver and skin as a proof-of-concept tissues, we show that readily available signature genes based on expression profiles of mouse cell types can be used to deconvolute the cellular composition of human GTEx tissues. We then deconvoluted 6,829 bulk RNA-seq samples corresponding to 28 GTEx tissues and show that we are able to quantify cellular heterogeneity, determining both the different cell types present in each of the tissues and how their proportions vary between samples of the same tissue type. Conducting eQTL analyses for GTEx liver and skin samples using cell type composition estimates as interaction terms, we identified thousands of novel genetic associations that had lower effect sizes and were cell-type-associated. We further show that cell-type-associated eQTLs in skin colocalize with melanoma, malignant neoplasm, and infection signatures, indicating variants that influence gene expression in distinct skin cell types play important roles in skin traits and disease. Overall, our study provides a framework to estimate the relative fractions of different cell types in GTEx tissues using signature genes from mouse cell types and functionally characterize human genetic variation that impacts gene expression in a cell-type-specific manner.

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