scholarly journals Protein structure-based gene expression signatures

2020 ◽  
Author(s):  
R. Rahman ◽  
Y. Xiong ◽  
J. G. C. van Hasselt ◽  
J. Hansen ◽  
E. A. Sobie ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Structure ◽  
Mrna Expression ◽  
Expression Patterns ◽  
Drug Effects ◽  
Tissue Expression ◽  
Structural Features ◽  
Biological Phenomena ◽  
Gene Expression Signatures ◽  
Cellular Phenotypes

AbstractGene expression signatures (GES) connect phenotypes to mRNA expression patterns, providing a powerful approach to define cellular identity, function, and the effects of perturbations. However, the use of GES has suffered from vague assessment criteria and limited reproducibility. The structure of proteins defines the functional capability of genes, and hence, we hypothesized that enrichment of structural features could be a generalizable representation of gene sets. We derive structural gene expression signatures (sGES) using features from various levels of protein structure (e.g. domain, fold) encoded by the transcribed genes in GES, to describe cellular phenotypes. Comprehensive analyses of data from the Genotype-Tissue Expression Project (GTEx), ARCHS4, and mRNA expression of drug effects on cardiomyocytes show that structural GES (sGES) are useful for identifying robust signatures of biological phenomena. sGES also enables the characterization of signatures across experimental platforms, facilitates the interoperability of expression datasets, and can describe drug action on cells.

scholarly journals Protein structure–based gene expression signatures

2021 ◽  
Vol 118 (19) ◽  
pp. e2014866118
Author(s):  
Rayees Rahman ◽  
Nicole Zatorski ◽  
Jens Hansen ◽  
Yuguang Xiong ◽  
J. G. Coen van Hasselt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Structure ◽  
Mrna Expression ◽  
Messenger Rna ◽  
Drug Effects ◽  
Tissue Expression ◽  
Structural Features ◽  
Phenotypic Characterization ◽  
Biological Phenomena ◽  
Gene Expression Signatures

Gene expression signatures (GES) connect phenotypes to differential messenger RNA (mRNA) expression of genes, providing a powerful approach to define cellular identity, function, and the effects of perturbations. The use of GES has suffered from vague assessment criteria and limited reproducibility. Because the structure of proteins defines the functional capability of genes, we hypothesized that enrichment of structural features could be a generalizable representation of gene sets. We derive structural gene expression signatures (sGES) using features from multiple levels of protein structure (e.g., domain and fold) encoded by the mRNAs in GES. Comprehensive analyses of data from the Genotype-Tissue Expression Project (GTEx), the all RNA-seq and ChIP-seq sample and signature search (ARCHS4) database, and mRNA expression of drug effects on cardiomyocytes show that sGES are useful for characterizing biological phenomena. sGES enable phenotypic characterization across experimental platforms, facilitates interoperability of expression datasets, and describe drug action on cells.

scholarly journals Early Response of CD8+ T Cells in COVID-19 Patients

2021 ◽  
Vol 11 (12) ◽  
pp. 1291
Author(s):  
Deni Ramljak ◽  
Martina Vukoja ◽  
Marina Curlin ◽  
Katarina Vukojevic ◽  
Maja Barbaric ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Mrna Expression ◽  
Cd8 T Cells ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Effector Memory ◽  
Healthy Controls ◽  
Ifn Γ

Healthy and controlled immune response in COVID-19 is crucial for mild forms of the disease. Although CD8+ T cells play important role in this response, there is still a lack of studies showing the gene expression profiles in those cells at the beginning of the disease as potential predictors of more severe forms after the first week. We investigated a proportion of different subpopulations of CD8+ T cells and their gene expression patterns for cytotoxic proteins (perforin-1 (PRF1), granulysin (GNLY), granzyme B (GZMB), granzyme A (GZMA), granzyme K (GZMK)), cytokine interferon-γ (IFN-γ), and apoptotic protein Fas ligand (FASL) in CD8+ T cells from peripheral blood in first weeks of SARS-CoV-2 infection. Sixteen COVID-19 patients and nine healthy controls were included. The absolute counts of total lymphocytes (p = 0.007), CD3+ (p = 0.05), and CD8+ T cells (p = 0.01) in COVID-19 patients were significantly decreased compared to healthy controls. In COVID-19 patients in CD8+ T cell compartment, we observed lower frequency effector memory 1 (EM1) (p = 0.06) and effector memory 4 (EM4) (p < 0.001) CD8+ T cells. Higher mRNA expression of PRF1 (p = 0.05) and lower mRNA expression of FASL (p = 0.05) at the fifth day of the disease were found in COVID-19 patients compared to healthy controls. mRNA expression of PRF1 (p < 0.001) and IFN-γ (p < 0.001) was significantly downregulated in the first week of disease in COVID-19 patients who progressed to moderate and severe forms after the first week, compared to patients with mild symptoms during the entire disease course. GZMK (p < 0.01) and FASL (p < 0.01) mRNA expression was downregulated in all COVID-19 patients compared to healthy controls. Our results can lead to a better understanding of the inappropriate immune response of CD8+ T cells in SARS-CoV2 with the faster progression of the disease.

Correlation of messenger RNA expression patterns of ERCC1, TS, EGFR, and VEGFR2 with KRAS and BRAF mutational status in advanced colorectal cancer: Implications for targeted therapies.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 383-383
Author(s):  
Martin K. H. Maus ◽  
Craig Stephens ◽  
Stephanie H. Astrow ◽  
Peter Philipp Grimminger ◽  
Dongyun Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Mrna Expression ◽  
Advanced Colorectal Cancer ◽  
Expression Patterns ◽  
Mrna Levels ◽  
Expression Levels ◽  
Mutational Status ◽  
Mrna Expression Levels ◽  
Gene Expression Levels

383 Background: Gene expression levels of ERCC1, TS, EGFR and VEGFR2 may have predictive value for the personalized use of standard chemotherapeutics as well as agents targeting the EGFR and VEGF pathways and the efficacy of EGFR directed monoclonal antibodies like panitumumab and cetuximab has been confirmed to be dependent on wt KRAS and wt BRAF in patients with advanced colorectal cancer. We investigated the correlations between KRAS/BRAF mutational status and the mRNA expression levels of these genes. Methods: Formalin-fixed paraffin-embedded tumor specimens from 600 patients with advanced colorectal adenocarcinoma were microdissected and DNA and RNA was extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. Results: Mt KRAS tumors had significantly lower TS and EGFR gene expression levels compared with wt KRAS (p<0,001), whereas mt BRAF tumors showed significantly increased TS and EGFR mRNA levels compared to wt BRAF (p<0,001). Mt BRAF tumors showed significantly higher mRNA levels than mt KRAS tumors (p<0,001). ERCC1 and VEGFR2 mRNA levels were significantly down-regulated in mt KRAS specimen (p<0,001), but showed no significant correlation with BRAF mutational status. Conclusions: KRAS and BRAF mutations are associated with opposite mRNA expression levels for TS and EGFR. Recently, resistance to BRAF inhibition in mt BRAF colorectal tumors has been shown in preclinical models to be associated with up-regulation of EGFR. Our data suggests that BRAF mutants are associated with high EGFR levels at the time of diagnosis, and not necessarily part of an acquired mechanism of resistance. Significantly lower mRNA expression levels of VEGFR2 in mt KRAS tumors may explain lower response to angiogenesis inhibition seen in the TML study.

scholarly journals Variability in porcine microRNA genes and its association with mRNA expression phenotypes

2020 ◽  
Author(s):  
Emilio Mármol-Sánchez ◽  
Dailu Guan ◽  
Raquel Quintanilla ◽  
Raul Tonda ◽  
Marcel Amills
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Binding Sites ◽  
Expression Patterns ◽  
Critical Role ◽  
Apical Region ◽  
Seed Region ◽  
Association Analyses ◽  
Mirna Genes ◽  
Wide Range

AbstractBackgroundMature microRNAs (miRNAs) play an important role in repressing the expression of a wide range of protein coding transcripts by promoting their degradation or inhibiting their translation into functional proteins. The presence of segregating polymorphisms inside miRNA loci and their corresponding 3’UTR binding sites might disrupt canonical conserved miRNA-mRNA pairing, thus modifying gene expression patterns.ResultsWe aimed to investigate the variability of miRNA genes and their putative binding sites by analyzing whole-genome sequences from 120 pigs and wild boars from Europe and Asia. In total, 285 SNPs residing within miRNA loci were detected. From these, 221 were located in precursor regions, whereas 52 and 12 mapped to mature and seed regions, respectively. Moreover, a total of 109,724 polymorphisms were identified in predicted 7mer-m8 miRNA binding sites within porcine 3’UTRs. A principal components analysis revealed a clear genetic divergence between Asian and European samples, which was particularly strong for 3’UTR sequences. We also observed that miRNA genes show reduced polymorphism compared with other non-miRNA regions. To assess the potential consequences of miRNA polymorphisms, we sequenced the genomes of 5 Duroc pigs and, by doing so, we identified 15 miRNA SNPs that were genotyped in the offspring (N = 345) of the five boars. Association analyses between miRNA SNPs and hepatic and muscle microarray data allowed us to identify 4 polymorphisms displaying significant associations. Particularly interesting was the rs319154814 polymorphism (G/A), located in the apical loop of the ssc-miR-326 precursor sequence. This polymorphism is predicted to cause a subtle hairpin rearrangement that improves the accessibility to processing enzymatic factors.ConclusionsPorcine miRNA genes show a reduced variability, particularly in the seed region which plays a critical role in miRNA binding. Although it is generally assumed that SNPs mapping to the seed region are the ones with the strongest consequences on mRNA expression, we show that a SNP mapping to the apical region of ssc-miR-326 is associated with the mRNA expression of several of its predicted targets. This result suggests that porcine miRNA variability mapping within and outside the seed region could have important regulatory effects on gene expression.

Development of gene expression signatures characterizing the tumor-immune interaction.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 205-205 ◽  
Author(s):  
Patrick Danaher ◽  
Sarah Warren ◽  
Alessandra Cesano
Keyword(s):  
Gene Expression ◽  
Candidate Genes ◽  
Tumor Cells ◽  
Expression Patterns ◽  
Sufficient Evidence ◽  
Training Procedure ◽  
Biological Processes ◽  
Immune Signaling ◽  
Gene Expression Signatures ◽  
Immune Oncology

205 Background: The efficacy of anti-tumor immunity depends on diverse factors, including not just abundance of immune cell populations but also activities of those populations and of tumor cells. Many of these processes are onerous to assay, but all are reflected in a tumor’s gene expression profile. Using a novel method, we develop gene expression signatures measuring a variety of biological processes underlying the tumor-immune interaction. These signatures fall into categories including antigen availability, structural barriers to immune infiltration, inhibitory signaling by both immune and tumor cells, inhibitory metabolism, pro-immune signaling, killing of tumor cells, tumor receptiveness to immune signaling, and tumor proliferation and death. Methods: We develop a method to train signatures of biological processed by synthesizing biological knowledge and large gene expression datasets. For a given process, we use literature searches and expert knowledge to derive lists of candidate genes. We then evaluate the co-expression of these candidate genes in data from The Cancer Genome Atlas (TCGA), discarding genes whose co-expression patterns are incompatible with their measuring their putative biological process. This approach safeguards the interpretability of our signatures: we only report signatures whose genes show evidence for measuring the desired biology. Finally, we further exploit co-expression patterns to obtain optimal weights for each signature gene. Results: We attempted to train signatures of over 30 biological processes involved in immune oncology. Of these, 17 candidate gene sets displayed sufficient evidence for measuring their putative biology. We show these signatures provide granular but intelligible descriptions of both immunotherapy datasets and single samples. We find they improve power in differential expression analyses and in training of predictors of drug response. Conclusions: The signatures we derive convert gene expression data into measurements of biological processes central to immune oncology, and they improve statistical power and interpretation of results in immunotherapy studies. Our training procedure ensures these signatures measure their intended biology.

scholarly journals Simultaneous Single-Cell In Situ Analysis of Human Adenovirus Type 5 DNA and mRNA Expression Patterns in Lytic and Persistent Infection

2017 ◽  
Vol 91 (11) ◽  
Author(s):  
Tomasz Krzywkowski ◽  
Sibel Ciftci ◽  
Farzaneh Assadian ◽  
Mats Nilsson ◽  
Tanel Punga
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Single Cell ◽  
Cell Population ◽  
Rolling Circle Amplification ◽  
Expression Patterns ◽  
Human Adenovirus ◽  
Viral Dna ◽  
Rolling Circle ◽  
Infected Cells

ABSTRACT An efficient adenovirus infection results in high-level accumulation of viral DNA and mRNAs in the infected cell population. However, the average viral DNA and mRNA content in a heterogeneous cell population does not necessarily reflect the same abundance in individual cells. Here, we describe a novel padlock probe-based rolling-circle amplification technique that enables simultaneous detection and analysis of human adenovirus type 5 (HAdV-5) genomic DNA and virus-encoded mRNAs in individual infected cells. We demonstrate that the method is applicable for detection and quantification of HAdV-5 DNA and mRNAs in short-term infections in human epithelial cells and in long-term infections in human B lymphocytes. Single-cell evaluation of these infections revealed high heterogeneity and unique cell subpopulations defined by differential viral DNA content and mRNA expression. Further, our single-cell analysis shows that the specific expression pattern of viral E1A 13S and 12S mRNA splice variants is linked to HAdV-5 DNA content in the individual cells. Furthermore, we show that expression of a mature form of the HAdV-5 histone-like protein VII affects virus genome detection in HAdV-5-infected cells. Collectively, padlock probes combined with rolling-circle amplification should be a welcome addition to the method repertoire for the characterization of the molecular details of the HAdV life cycle in individual infected cells. IMPORTANCE Human adenoviruses (HAdVs) have been extensively used as model systems to study various aspects of eukaryotic gene expression and genome organization. The vast majority of the HAdV studies are based on standard experimental procedures carried out using heterogeneous cell populations, where data averaging often masks biological differences. As every cell is unique, characteristics and efficiency of an HAdV infection can vary from cell to cell. Therefore, the analysis of HAdV gene expression and genome organization would benefit from a method that permits analysis of individual infected cells in the heterogeneous cell population. Here, we show that the padlock probe-based rolling-circle amplification method can be used to study concurrent viral DNA accumulation and mRNA expression patterns in individual HAdV-5-infected cells. Hence, this versatile method can be applied to detect the extent of infection and virus gene expression changes in different HAdV-5 infections.

scholarly journals Changes in Gene Expression during Pituitary Morphogenesis and Organogenesis in the Chick Embryo

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 989-1000 ◽  
Author(s):  
Monika Proszkowiec-Weglarz ◽  
Stacy E. Higgins ◽  
Tom E. Porter
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Anterior Pituitary ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Mrna Levels ◽  
Pituitary Development ◽  
Excellent Model ◽  
Functional Development

The anterior pituitary gland plays an important role in the regulation of many physiological processes. Formation of Rathke's pouch (RP), the precursor of the anterior pituitary, involves evagination of the oral ectoderm in a multi-step process regulated by cell interactions, signaling pathways, and transcription factors. Chickens are an excellent model to study development because of the availability of large sample sizes, accurate timing of development, and embryo accessibility. The aim of this study was to quantify mRNA expression patterns in the developing chicken anterior pituitary to evaluate the chicken embryo as a model for mammalian pituitary development. The expression profiles of 16 genes differentially expressed in RP and neuroectoderm were determined in this study. Among these, Pitx1, Pitx2, and Hesx1 mRNA levels were high on embryonic days (e) 2.5 to e3 in RP and decreased during development. Expression of Pit1 and Tbx19 mRNA in RP reached the highest levels by e7 and e6.5, respectively. Levels of glycoprotein subunit α mRNA increased beginning at e4. FGF8 mRNA showed the highest expression at e3 to e3.5 in neuroectoderm. BMP2 showed slight decreases in mRNA expression in both tissues during development, while Isl1 and Noggin mRNA expression increased in later development. Taken together, we present the first quantitative transcriptional profile of pituitary organogenesis. Our results will help further understanding of the functional development of this gland. Moreover, because of the high similarity in gene expression patterns observed between chicken and mouse, chickens could serve as an excellent model to study genetic and molecular mechanisms underlying pituitary development.

scholarly journals Predicting Cellular Drug Sensitivity using Conditional Modulation of Gene Expression

2021 ◽  
Author(s):  
Will Connell ◽  
Michael Keiser
Keyword(s):  
Gene Expression ◽  
Small Molecule ◽  
Drug Sensitivity ◽  
Expression Patterns ◽  
Structural Features ◽  
Precision Oncology ◽  
Transcriptional Signature ◽  
Ongoing Work ◽  
Important Challenge ◽  
Modulation Of Gene Expression

AbstractSelecting drugs most effective against a tumor’s specific transcriptional signature is an important challenge in precision medicine. To assess oncogenic therapy options, cancer cell lines are dosed with drugs that can differentially impact cellular viability. Here we show that basal gene expression patterns can be conditioned by learned small molecule structure to better predict cellular drug sensitivity, achieving an R2 of 0.7190±0.0098 (a 5.61% gain). We find that 1) transforming gene expression values by learned small molecule representations outperforms raw feature concatenation, 2) small molecule structural features meaningfully contribute to learned representations, and 3) an affine transformation best integrates these representations. We analyze conditioning parameters to determine how small molecule representations modulate gene expression embeddings. This ongoing work formalizes in silico cellular screening as a conditional task in precision oncology applications that can improve drug selection for cancer treatment.

scholarly journals Tissue, age, sex, and disease patterns of matrisome expression in GTEx transcriptome data

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tim O. Nieuwenhuis ◽  
Avi Z. Rosenberg ◽  
Matthew N. McCall ◽  
Marc K. Halushka
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Tissue Expression ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Normal Tissues ◽  
Disease Patterns ◽  
Generalized Matrix ◽  
Gene Transcripts ◽  
Matrix Control

AbstractThe extracellular matrix (ECM) has historically been explored through proteomic methods. Whether or not global transcriptomics can yield meaningful information on the human matrisome is unknown. Gene expression data from 17,382 samples across 52 tissues, were obtained from the Genotype-Tissue Expression (GTEx) project. Additional datasets were obtained from The Cancer Genome Atlas (TCGA) program and the Gene Expression Omnibus for comparisons. Gene expression levels generally matched proteome-derived matrisome expression patterns. Further, matrisome gene expression properly clustered tissue types, with some matrisome genes including SERPIN family members having tissue-restricted expression patterns. Deeper analyses revealed 382 gene transcripts varied by age and 315 varied by sex in at least one tissue, with expression correlating with digitally imaged histologic tissue features. A comparison of TCGA tumor, TCGA adjacent normal and GTEx normal tissues demonstrated robustness of the GTEx samples as a generalized matrix control, while also determining a common primary tumor matrisome. Additionally, GTEx tissues served as a useful non-diseased control in a separate study of idiopathic pulmonary fibrosis (IPF) matrix changes, while identifying 22 matrix genes upregulated in IPF. Altogether, these findings indicate that the transcriptome, in general, and GTEx in particular, has value in understanding the state of organ ECM.

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