Pathway Mapping Tools for Analysis of High Content Data

Ekins, Sean; Nikolsky, Yuri; Bugrim, Andrej; Kirillov, Eugene; Nikolskaya, Tatiana

doi:10.1385/1-59745-217-3:319

Cited by 185 publications

(217 citation statements)

References 88 publications

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“…Molecular signaling across tissues was inferred from gene expression information collected in the present study and a priori knowledge of protein-protein interactions. The protein interaction database and the network models were extracted and built using the MetaCore software from GeneGo (66).…”

Section: Methodsmentioning

confidence: 99%

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

Biase

Rabel

Guillomot

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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A major unresolved issue in the cloning of mammals by somatic cell nuclear transfer (SCNT) is the mechanism by which the process fails after embryos are transferred to the uterus of recipients before or during the implantation window. We investigated this problem by using RNA sequencing (RNA-seq) to compare the transcriptomes in cattle conceptuses produced by SCNT and artificial insemination (AI) at day (d) 18 (preimplantation) and d 34 (postimplantation) of gestation. In addition, endometrium was profiled to identify the communication pathways that might be affected by the presence of a cloned conceptus, ultimately leading to mortality before or during the implantation window. At d 18, the effects on the transcriptome associated with SCNT were massive, involving more than 5,000 differentially expressed genes (DEGs). Among them are 121 genes that have embryonic lethal phenotypes in mice, cause defects in trophoblast and placental development, and/or affect conceptus survival in mice. In endometria at d 18, <0.4% of expressed genes were affected by the presence of a cloned conceptus, whereas at d 34, ∼36% and <0.7% of genes were differentially expressed in intercaruncular and caruncular tissues, respectively. Functional analysis of DEGs in placental and endometrial tissues suggests a major disruption of signaling between the cloned conceptus and the endometrium, particularly the intercaruncular tissue. Our results support a "bottleneck" model for cloned conceptus survival during the periimplantation period determined by gene expression levels in extraembryonic tissues and the endometrial response to altered signaling from clones. somatic cell nuclear transfer | conceptus | placentation | conceptus-maternal communication I n cattle, as in other mammals, exquisitely orchestrated physiological changes of the conceptus and uterus are necessary for a successful pregnancy. Synchronization of the complex events at the time of implantation relies on the timed release of molecular signals from the conceptus and the endometrium. Embryo-derived IFN-τ (IFNT) is the major signal of pregnancy in cattle, preventing luteolysis and regulating the expression of genes that are responsible for promoting local changes in the endometrium to accommodate the conceptus (1-3). In females, progesterone is the major driver of endometrial changes that prepare the uterus for conceptus implantation (4, 5). In addition to IFNT and progesterone, signaling between the bovine conceptus and the endometrium is bidirectional, and involves several pathways that work concomitantly (6) for the successful establishment of pregnancy.Independent studies have shown that the majority of embryonic losses in cattle occur during the period that spans embryo cleavage until the attachment of the blastocyst to the endometrium (7). The reasons for these losses remain unclear and likely result from several factors, including embryonic lethal genes (8, 9), environmental stressors (7), and endometrial condition (10). Cloning of cattle by somatic cell nuclear transfer ...

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Section: Methodsmentioning

confidence: 99%

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

Biase

Rabel

Guillomot

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This analysis was performed using the Metacore ™ software coupled to the MetaBase ™ interactions database (free trial available at www.genego.com) and enabled with network building capabilities described earlier (Ekins et al 2007). Basic principles and algorithms of such meta-analysis of gene expression data are described elsewhere (Ekins et al 2006).…”

Section: Meta-analysis By Interactome Reconstructionmentioning

confidence: 99%

Differential gene expression profiling of large and small retinal ganglion cells

Ivanov

Dvoriantchikova

Barakat

et al. 2008

Journal of Neuroscience Methods

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Different sub-populations of retinal ganglion cells (RGCs) vary in their sensitivity to pathological conditions such as retinal ischemia, diabetic retinopathy and glaucoma. Comparative Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. transcriptomic analysis of such groups will likely reveal molecular determinants of differential sensitivity to stress. However, gene expression profiling of primary neuronal sub-populations represent a challenge due to the cellular heterogeneity of retinal tissue. In this manuscript, we report the use of a fluorescent neural tracer to specifically label and selectively isolate RGCs with different soma sizes by fluorescence-activated cell sorting (FACS) for the purpose of differential gene expression profiling. We identified 145 genes that were more active in the large RGCs and 312 genes in the small RGCs. Differential data were validated by quantitative RT-PCR, several corresponding proteins were confirmed by immunohistochemistry. Functional characterization revealed differential activity of genes implicated in synaptic transmission, neurotransmitter secretion, axon guidance, chemotaxis, ion transport and tolerance to stress. An in silico reconstruction of cellular networks suggested that differences in pathway activity between the two sub-populations of RGCs are controlled by networks interconnected by SP-1, Erk2(MAPK1), Egr1, Egr2 and, potentially, regulated via transcription factors C/EBPbeta, HSF1, STAT1-and cMyc. The results show that FACS-aided purification of retrogradely labeled cells can be effectively utilized for transcriptional profiling of adult retinal neurons. NIH Public Access

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“…At the core of functional interpretation of omics data is the knowledge (such as annotations and literature data) provided to the biological objects, being genes, mRNAs, or proteins from various molecular databases. Meanwhile bioinformatics tools have been developed for analyzing and interpreting the large lists of genes or proteins, such as DAVID , BABELOMICS (Al-Shahrour et al, 2005), Ingenuity (http://www.ingenuity.com/) and GeneGO (Ekins et al, 2007) for function and pathway analysis of large-scale data.…”

Section: Introductionmentioning

confidence: 99%

Integrated Bioinformatics for Radiation-Induced Pathway Analysis from Proteomics and Microarray Data

Hu¹,

Huang²,

Cheema³

et al. 2008

J Proteomics Bioinform

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Functional analysis and interpretation of large-scale proteomics and gene expression data require effective use of bioinformatics tools and public knowledge resources coupled with expert-guided examination. An integrated bioinformatics approach was used to analyze cellular pathways in response to ionizing radiation. ATM, or ataxia-telangiectasia mutated , a serine-threonine protein kinase, plays critical roles in radiation responses, including cell cycle arrest and DNA repair. We analyzed radiation responsive pathways based on 2D-gel/MS proteomics and microarray gene expression data from fibroblasts expressing wild type or mutant ATM gene. The analysis showed that metabolism was significantly affected by radiation in an ATM dependent manner. In particular, purine metabolic pathways were differentially changed in the two cell lines. The expression of ribonucleoside-diphosphate reductase subunit M2 (RRM2) was increased in ATM-wild type cells at both mRNA and protein levels, but no changes were detected in ATM-mutated cells. Increased expression of p53 was observed 30min after irradiation of the ATM-wild type cells. These results suggest that RRM2 is a downstream target of the ATM-p53 pathway that mediates radiation-induced DNA repair. We demonstrated that the integrated bioinformatics approach facilitated pathway analysis, hypothesis generation and target gene/protein identification.

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Pathway Mapping Tools for Analysis of High Content Data

Cited by 185 publications

References 88 publications

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

Differential gene expression profiling of large and small retinal ganglion cells

Integrated Bioinformatics for Radiation-Induced Pathway Analysis from Proteomics and Microarray Data

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