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PubMed2006

Nonparametric pathway-based regression models for analysis of genomic data.

High-throughout genomic data provide an opportunity for identifying pathways and genes that are related to various clinical phenotypes. Besides these genomic data, another valuable source of data is the biological knowledge about genes and pathways that might be related to the phenotypes of many complex diseases. Databases of such knowledge are often called the metadata. In microarray data analysis, such metadata are currently explored in post hoc ways by gene set enrichment analysis but have hardly been utilized in the modeling step. We propose to develop and evaluate a pathway-based gradient descent boosting procedure for nonparametric pathways-based regression (NPR) analysis to efficiently integrate genomic data and metadata. Such NPR models consider multiple pathways simultaneously and allow complex interactions among genes within the pathways and can be applied to identify pathways and genes that are related to variations of the phenotypes. These methods also provide an alternative to mediating the problem of a large number of potential interactions by limiting analysis to biologically plausible interactions between genes in related pathways. Our simulation studies indicate that the proposed boosting procedure can indeed identify relevant pathways. Application to a gene expression data set on breast cancer distant metastasis identified that Wnt, apoptosis, and cell cycle-regulated pathways are more likely related to the risk of distant metastasis among lymph-node-negative breast cancer patients. Results from analysis of other two breast cancer gene expression data sets indicate that the pathways of Metalloendopeptidases (MMPs) and MMP inhibitors, as well as cell proliferation, cell growth, and maintenance are important to breast cancer relapse and survival. We also observed that by incorporating the pathway information, we achieved better prediction for cancer recurrence.

Adult↗
PubMed2004

Genome-wide analysis of the unfolded protein response in fibroblasts from congenital disorders of glycosylation type-I patients.

Congenital disorders of glycosylation (CDG) are a family of diseases characterized by defects of N-linked glycosylation. In CDG-I, several genetic defects cause a shortage of dolichol-linked oligosaccharides, which leads to underglycosylation of nascent glycoproteins. N-linked glycosylation is important for proper folding and trafficking of glycoproteins. Inhibition of glycosylation results in the buildup of misfolded proteins in the endoplasmic reticulum, which induces a protective reaction known as the unfolded protein response (UPR). To investigate whether UPR components are induced in CDG, we have performed a transcriptome analysis of primary fibroblasts from unaffected control subjects and from CDG-I patients using oligonucleotide gene expression arrays. The stress imposed by CDG was also compared with the stress induced by tunicamycin and glucose deprivation. Whereas tunicamycin elicited a strong transcriptional response typical for the UPR, CDG fibroblasts displayed a qualitatively similar yet moderate induction of genes encoding components of the UPR. Among these genes, the PERK kinase inhibitor DNAJC3/P58(IPK) gene showed the highest induction throughout all CDG-I types tested. This was paralleled by elevated expression of genes involved in amino acid biosynthesis and transport, which defined a new component of the cellular response to glycosylation stress.

Cells, Cultured↗
PubMed2006

Physiological genomics of cardiac disease: quantitative relationships between gene expression and left ventricular hypertrophy.

The pathogenesis of cardiac left ventricular hypertrophy and failure is poorly defined due to the complexity of the disease phenotype. To gain a better understanding of the relationship between gene expression and left ventricular hypertrophy, we employed a quantitative approach to identify genes with expression patterns that correlate in a numerically continuous manner with parameters of cardiac structure and function in a mouse model of left ventricular hypertrophy due to transverse aortic constriction. Several genes showed expression patterns that were significantly correlated (Pearson's correlation coefficient) with measurements of left ventricular weight, left ventricular wall thickness, and diastolic dimension. We validated our findings in two independent data sets and in a small subset of genes by real-time RT-PCR. Of genes with significant correlations to numerically continuous measurements of hypertrophy, we found enrichment for genes encoding extracellular matrix, growth-related and secreted proteins in the directly correlated subset, and for genes encoding mitochondria and metabolic/fatty acid oxidation proteins in the inversely correlated subset. The results of this filtering strategy suggest that this subset of transcripts with quantitative relationships between gene expression and left ventricular hypertrophy represents potentially important pathways that contribute to the progression to heart failure and are thus candidates for follow-up and functional analysis.

Animals↗
PubMed2000

Relationship of codon bias to mRNA concentration and protein length in Saccharomyces cerevisiae.

In 1982, Ikemura reported a strikingly unequal usage of different synonymous codons, in five Saccharomyces cerevisiae nuclear genes having high protein levels. To study this trend in detail, we examined data from three independent studies that used oligonucleotide arrays or SAGE to estimate mRNA concentrations for nearly all genes in the genome. Correlation coefficients were calculated for the relationship of mRNA concentration to four commonly used measures of synonymous codon usage bias: the codon adaptation index (CAI), the codon bias index (CBI), the frequency of optimal codons (F(op)), and the effective number of codons (N(c)). mRNA concentration was best approximated as an exponential function of each of these four measures. Of the four, the CAI was the most strongly correlated with mRNA concentration (r(s)=0.62+/-0.01, n=2525, p<10(-17)). When we controlled for CAI, mRNA concentration and protein length were negatively correlated (partial r(s)=-0.23+/-0.01, n=4765, p<10(-17)). This may result from selection to reduce the size of abundant proteins to minimize transcriptional and translational costs. When we controlled for mRNA concentration, protein length and CAI were positively correlated (partial r(s)=0.16+/-0.01, n=4765, p<10(-17)). This may reflect more effective selection in longer genes against missense errors during translation. The correlation coefficients between the mRNA levels of individual genes, as measured by different investigators and methods, were low, in the range r(s)=0.39-0.68.

Codon↗
PubMed2003

Gene expression in cancer: the application of microarrays.

Genome-wide monitoring of gene expression using DNA microarrays represents one of the latest breakthroughs in experimental molecular biology and provides unprecedented opportunity to explore the biological processes underlying human diseases by providing a comprehensive survey of a cell's transcriptional landscape. In the cancer field, this revolutionary technology allows the simultaneous assessment of the transcription of tens of thousands of genes, and of their relative expression between normal cells and malignant cells. As microarray analysis emerges from its infancy, there is widespread hope that microarrays will significantly impact on our ability to explore the genetic changes associated with cancer etiology and development, and ultimately lead to the discovery of new biomarkers for disease diagnosis and prognosis prediction, and of new therapeutic tools. This review provides an overview of microarray technology, specifically in the context of cancer research and describes some of its recent applications to the study of cancer. In addition, the challenges of translating microarray findings into molecular cancer diagnosis and prognosis tools, with the potential of altering clinical practice through individualized cancer care and ultimately of contributing to the battle against cancer, are discussed.

Cytogenetic Analysis↗
PubMed2026

A Practical Workflow for Spatial Transcriptomics Data Analysis: From Data Acquisition to Advanced Analyses.

Spatial transcriptomics (ST) profiles genome-wide gene expression while preserving the two-dimensional spatial context of mRNA molecules within tissue sections, enabling studies of tissue architecture and microenvironment-associated biology. However, ST analysis remains challenging because data import, quality control, integration, deconvolution, spatial statistics, and visualization often require multiple software environments and reproducible parameter choices. This protocol presents a practical computational workflow for public ST datasets in R, beginning with data acquisition and software setup and proceeding through Seurat-based data loading, quality control, normalization, multi-sample integration, clustering, and spatially variable gene analysis. The workflow then applies complementary deconvolution strategies, including reference-guided SPOTlight analysis and unsupervised STdeconvolve topic modeling, followed by Giotto-based spatial cell-cell communication analysis and interactive region-of-interest (ROI) selection using a custom Python Dash application. By emphasizing script-based execution, explicit parameter rationales, expected outputs, and troubleshooting checkpoints, the protocol provides an adaptable framework for standard array-based ST datasets and related platforms after dataset- and platform-specific parameter evaluation.

Spatial Transcriptomics↗
PubMed2007

The application of proteomics and genomics to the study of age-related neurodegeneration and neuroprotection.

The present study aimed to acquire more information on aging-related alterations, using proteomic and genomic analyses of hippocampus from young (8 months) and old (27 months) rats. In the old rats, the proteomic analysis identified changes in proteins related to the iron-mediated oxidative stress (OS) pathway, including reduction in antioxidant enzymes (e.g., peroxiredoxin, cytochrome c oxidase) and induction of ferritin. Furthermore, the neurofilament light peptide, associated with neurodegenerative processes, was enhanced and binding/ chaperone proteins were altered in old vs. young rats. At the genes levels, significant molecular changes related to neurodegeneration were identified in aged rat hippocampus. Thus, the effects of the potent neuroprotective compounds, the anti-Parkinson drug, rasagiline and the anti-Alzheimer drug, ladostigil (1 mg/kg, for 30 days) on gene expression in the hippocampus were further investigated. Both drugs reversed the effect of aging on the expression of various mitochondrial and key regulator genes involved in neurodegeneration, cell survival, synaptogenesis, oxidation, and metabolism. These results support the hypothesis that OS and mitochondrial dysfunction may play a pivotal role in aging and age-associated neurodegenerative diseases, and can serve as potential clinical targets for future therapy.

Aging↗
PubMed2003

Chlamydomonas reinhardtii genome project. A guide to the generation and use of the cDNA information.

The National Science Foundation-funded Chlamydomonas reinhardtii genome project involves (a) construction and sequencing of cDNAs isolated from cells exposed to various environmental conditions, (b) construction of a high-density cDNA microarray, (c) generation of genomic contigs that are nucleated around specific physical and genetic markers, (d) generation of a complete chloroplast genome sequence and analyses of chloroplast gene expression, and (e) the creation of a Web-based resource that allows for easy access of the information in a format that can be readily queried. Phases of the project performed by the groups at the Carnegie Institution and Duke University involve the generation of normalized cDNA libraries, sequencing of cDNAs, analysis and assembly of these sequences to generate contigs and a set of predicted unique genes, and the use of this information to construct a high-density DNA microarray. In this paper, we discuss techniques involved in obtaining cDNA end-sequence information and the ways in which this information is assembled and analyzed. Descriptions of protocols for preparing cDNA libraries, assembling cDNA sequences and annotating the sequence information are provided (the reader is directed to Web sites for more detailed descriptions of these methods). We also discuss preliminary results in which the different cDNA libraries are used to identify genes that are potentially differentially expressed.

Animals↗
PubMed2005

Functional Genomics meets neurodegenerative disorders. Part II: application and data integration.

The transcriptomic and proteomic techniques presented in part I (Functional Genomics meets neurodegenerative disorders. Part I: transcriptomic and proteomic technology) of this back-to-back review have been applied to a range of neurodegenerative disorders, including Huntington's disease (HD), Prion diseases (PrD), Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), frontotemporal dementia (FTD) and Parkinson's disease (PD). Samples have been derived either from human brain and cerebrospinal fluid, tissue culture cells or brains and spinal cord of experimental animal models. With the availability of huge data sets it will firstly be a major challenge to extract meaningful information and secondly, not to obtain contradicting results when data are collected in parallel from the same source of biological specimen using different techniques. Reliability of the data highly depends on proper normalization and validation both of which are discussed together with an outlook on developments that can be anticipated in the future and are expected to fuel the field. The new insight undoubtedly will lead to a redefinition and subdivision of disease entities based on biochemical criteria rather than the clinical presentation. This will have important implications for treatment strategies.

Animals↗
PubMed2006

Genomic and metabolic studies of the impact of probiotics on a model gut symbiont and host.

Probiotics are deliberately ingested preparations of live bacterial species that confer health benefits on the host. Many of these species are associated with the fermentation of dairy products. Despite their increasing use, the molecular details of the impact of various probiotic preparations on resident members of the gut microbiota and the host are generally lacking. To address this issue, we colonized germ-free mice with Bacteroides thetaiotaomicron, a prominent component of the adult human gut microbiota, and Bifidobacterium longum, a minor member but a commonly used probiotic. Simultaneous whole genome transcriptional profiling of both bacterial species in their gut habitat and of the intestinal epithelium, combined with mass-spectrometric analysis of habitat-associated carbohydrates, revealed that the presence of B. longum elicits an expansion in the diversity of polysaccharides targeted for degradation by B. thetaiotaomicron (e.g., mannose- and xylose-containing glycans), and induces host genes involved in innate immunity. Although the overall transcriptome expressed by B. thetaiotaomicron when it encounters B. longum in the cecum is dependent upon the genetic background of the mouse (as assessed by a mixed analysis of variance [ANOVA] model of co-colonization experiments performed in NMRI and C57BL/6J animals), B. thetaiotaomicron's expanded capacity to utilize polysaccharides occurs independently of host genotype, and is also observed with a fermented dairy product-associated strain, Lactobacillus casei. This gnotobiotic mouse model provides a controlled case study of how a resident symbiont and a probiotic species adapt their substrate utilization in response to one another, and illustrates both the generality and specificity of the relationship between a host, a component of its microbiota, and intentionally consumed microbial species.

Animals↗
PubMed2004

A global approach to tumor immunology.

Biological and clinical advances in the understanding of tumor immunology suggest that immune responsiveness of human tumors is a complex biological phenomenon that could be best studied by a real-time comparison of tumor/host interactions in the tumor microenvironment through a high-throughput discovery-driven approach. This conclusion is derived from our recognition that too many hypotheses or, in other words, no solid single hypothesis exist, based on experimental results, to further drive experimentation in human subjects. Functional genomic studies entertained during the last few years consolidated the belief that in humans the interactions between tumor and immune cells are too complex to be approached exclusively with a hypothesis driven method. We believe that immune cells suit cancer cells in a Yin and Yang balance by opposing and yet mutually depending on each other. Indeed, immune infiltration in tumors may play a dual role modulating in different circumstances cancer cell growth or destruction through a physiological modulation of inflammation. It is reasonable to question what induces inflammation at the tumor site. We hypothesize that inflammation is primarily driven by the phenotype of tumor cells that can modulate their microenvironment through cell-to-cell interactions or the secretion of soluble factors. Thus, in analogy the observation of immune cells within tumors parallels the presence of paramedics, police and firemen at the scene of an accident, which is reactive to and not causative of the occurrence. In this review we will explore this hypothesis by reporting and summarizing most of our recent work in the frame of available literature on the subject.

Adjuvants, Immunologic↗
PubMed2006

Imprinted status of pleomorphic adenoma gene-like I and paternal expression gene 10 genes in pigs.

Genomic imprinting is theorized to exist in all placental mammals and some marsupials. Imprinted genes play important roles in the regulation of fetal growth, development, and postnatal behavior, but the study of imprinted genes has been limited in livestock. In this study, the polymorphism-based approach was used to detect the expression patterns of the porcine pleomorphic adenoma gene-like I (PLAGL1) and paternal expression gene 10 (PEG10) genes. Single nucleotide polymorphisms in the exons were detected between the Meishan and Large White breeds in the PLAGL1 and PEG10 genes. The polymorphisms were used to determine the monoallelic or biallelic expression with reverse transcription-PCR-RFLP in 44 tissues from 4 heterozygous pigs (based on SNP). Imprinting analysis indicated that the PLAGL1 and PEG10 genes were both paternally expressed in all tissues tested (heart, liver, spleen, lung, kidney, stomach, small intestine, skeletal muscle, fat, uterus, and ovary). Our study showed that the method of identifying polymorphic transcripts with reverse transcription-PCR-RFLP may be beneficial for detecting the imprinting status of some candidate imprinted genes.

Animals↗
PubMed2006

Genome-wide analyses show that nuclear and cytoplasmic RNA levels are differentially affected by dioxin.

The aryl hydrocarbon receptor (AHR) mounts the body's main molecular defense against environmental toxicants by inducing a battery of genes encoding xenobiotic metabolizing proteins. The AHR is activated by polycyclic aromatic hydrocarbon toxicants, including the pervasive teratogen and carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin). The TCDD-activated AHR significantly changes the cytoplasmic mRNA levels of hundreds of genes, but little is known of the mechanism by which the activated AHR causes such a strong effect on global gene expression. We used high-density microarrays to compare nuclear and cytoplasmic RNA levels from untreated and TCDD-treated mouse embryonic fibroblasts (MEF) to test the hypotheses that (1) TCDD has a large impact on nuclear RNA levels and (2) that cytoplasmic RNA levels are dependent on nuclear RNA levels. We found that nuclear RNA levels are strongly affected by TCDD, and that nuclear and cytoplasmic RNA levels are only weakly correlated, indicating that other regulatory mechanisms are controlling cytoplasmic RNA levels. The nuclear RNAs most affected by TCDD encode proteins involved in nuclear RNA processing and transcription. We conclude that although the AHR regulates key xenobiotic metabolizing genes at the transcriptional level, a larger impact of the TCDD-activated AHR may be at post-transcriptional levels.

Animals↗
PubMed2002

Analysis of acute myelogenous leukemia: preparation of samples for genomic and proteomic analyses.

During the last decade, several large clinical studies have demonstrated that analysis of chromosomal abnormalities is an essential basis for therapeutic decisions in patients with acute myelogenous leukemia (AML), and cytogenetic studies should now be regarded as mandatory both for routine treatment and as a part of clinical investigations in AML. However, new techniques for detailed genetic characterization and analysis of gene expression as well as protein modulation will become important in the further classification of AML subsets and the development of risk-adapted therapeutic strategies. In this context, we emphasize the importance of population-based clinical studies as a basis for future therapeutic guidelines. Such studies will then require the inclusion of patients at small clinical centers without specialized hematological research laboratories. To document a high and uniform quality of the laboratory investigations, it will be necessary to collect material for later analysis in selected laboratories. In this article, we describe current methods for collection of biological samples that can be used for later preparation of DNA, RNA, and proteins. With the use of gradient-separated AML cells, it should be possible to establish the necessary techniques for collection and handling of biological samples even at smaller centers, and complete collections from all included patients should then be possible even in population-based clinical studies.

Cytogenetic Analysis↗
PubMed2005

Comparative genomics on ROR1 and ROR2 orthologs.

Transmembrane proteins with extracellular Frizzled domain, such as ROR1, ROR2, MUSK, MFRP, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9 and FZD10, are key molecules for WNT signaling network. Here, comparative integromics analyses on ROR1 and ROR2 orthologs were performed by using bioinformatics. Zebrafish ror2 gene, consisting of nine exons, was identified within CR-450684.3 genome sequence. CV490605.1 EST corresponded to the 5'-end of zebrafish ror2 mRNA, and BM533602.1 EST corresponded to the 3'-end. Zebrafish ror2 gene was found to encode a 939-aa transmembrane protein, showing 71.7% and 56.2% total amino-acid identity with human ROR2 and ROR1, respectively. Immunoglobulin-like domain, Frizzled domain, Kringle domain within the extracellular region, tyrosine kinase domain, Ror homology C-terminal (RORHC) domain and juxta-C-terminal LLGD motif within the cytoplasmic region were conserved among vertebrate ROR1 and ROR2 orthologs. SH2 binding site within the RORHC domain was conserved among vertebrate ROR2 orthologs, but not among vertebrate ROR1 orthologs. ROR1 mRNA was expressed in embryonic stem (ES) cells, infant brain, renal cancer, and colon cancer. ROR2 mRNA was expressed in parathyroid, testis, uterus, and also in diffuse type gastric cancer with signet ring cell features. ROR2 promoter rather than ROR1 promoter was more evolutionarily conserved. WNT5A and ROR family receptors, co-expressed in ES cells and gastric cancer, are implicated in the planar cell polarity (PCP) pathway. ROR1 and ROR2 are the pharmacogenomics targets in the fields of stem cell biology and oncology.

Amino Acid Sequence↗
PubMedDate not supplied

Human endometrial receptivity: a genomic approach.

The endometrium is a specialized tissue, hormonally-regulated, that is non-adhesive for embryos throughout most of the menstrual cycle in humans and other primates. Thus, endometrial receptivity is a self-limited period in which the endometrial epithelium (EE) acquires a functional and transient ovarian steroid-dependent status. The luminal EE acquires the ability to adhere (receptivity) the developing human blastocyst during this period due mainly to the presence of progesterone after appropriate 17beta-oestradiol priming. This status is a key element for embryonic implantation and appears to be closely associated with morphological and biochemical changes of EE cells. This specific time window is thought to be open after 4-5 days and closes after 9-10 days of progesterone production or administration, creating a physiological window of receptivity limited to days 19-24 of the menstrual cycle in humans. The scientific knowledge of the endometrial receptivity process is fundamental for the understanding of the human reproduction, but, so far, none of the proposed biochemical markers for endometrial receptivity have been proved clinically useful. In this work new strategies are presented based on molecular biology technologies that aim to clarify the fragmented information in this field using differential display, quantitative PCR and cDNA microarray analysis of endometrial epithelial-derived cell lines and endometrial samples to investigate the hierarchy at the mRNA level of molecules implicated in the process of endometrial receptivity.

Blastocyst↗
PubMed2004

Widespread RNA editing of embedded alu elements in the human transcriptome.

More than one million copies of the approximately 300-bp Alu element are interspersed throughout the human genome, with up to 75% of all known genes having Alu insertions within their introns and/or UTRs. Transcribed Alu sequences can alter splicing patterns by generating new exons, but other impacts of intragenic Alu elements on their host RNA are largely unexplored. Recently, repeat elements present in the introns or 3'-UTRs of 15 human brain RNAs have been shown to be targets for multiple adenosine to inosine (A-to-I) editing. Using a statistical approach, we find that editing of transcripts with embedded Alu sequences is a global phenomenon in the human transcriptome, observed in 2674 ( approximately 2%) of all publicly available full-length human cDNAs (n = 128,406), from >250 libraries and >30 tissue sources. In the vast majority of edited RNAs, A-to-I substitutions are clustered within transcribed sense or antisense Alu sequences. Edited bases are primarily associated with retained introns, extended UTRs, or with transcripts that have no corresponding known gene. Therefore, Alu-associated RNA editing may be a mechanism for marking nonstandard transcripts, not destined for translation.

Alternative Splicing↗
PubMed2001

A comparison of microarray databases.

Microarray technology has become one of the most important functional genomics technologies. A proliferation of microarray databases has resulted. It can be difficult for researchers exploring this technology to know which bioinformatics systems best meet their requirements. In order to obtain a better understanding of the available systems, a survey and comparative analysis of microarray databases was undertaken. The survey included databases that are currently available, as well as databases that should become available in early 2001. Databases fall into three categories: (i) those that can be installed locally, (ii) those available for public data submission and (iii) those available for public query. Developers of microarray gene-expression databases were asked questions regarding the scope and availability of their database, its system requirements, its future compliance with MGED (Microarray Gene Expression Database) standards, and its associated analytical tools. Participants included AMAD (Stanford/Berkeley/UCSF), ArrayExpress (EBI), ChipDB (MIT/Whitehead), GeneX (NCGR), GeNet (Silicon Genetics), GeneDirector (BioDiscovery), GEO (NCBI), GXD (Jackson Laboratory), mAdb (NCI), maxdSQL (University of Manchester), NOMAD (UCSF), RAD (University of Pennsylvania) and SMD (Stanford University). Other database developers were contacted but data was not available at the time of manuscript preparation. Each database fulfils a different role, reflecting the widely varying needs of microarray users.

Animals↗