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Comprehensive Microbiome Analyses for Regenerative Endodontic Therapy.

INTRODUCTION: Comprehensive microbiome analyses include the study of all microbial taxa, including bacteria, archaea, viruses, and fungi, as well as their functional activities and antibiotic resistance gene expression. Regenerative endodontic therapy presents a clinical situation where the most effective antimicrobial approaches are needed in order to ensure clinical success. METHODS AND RESULTS: In this paper, different contemporary technologies for the identification of endodontic microorganisms, such as with next generation sequencing, and their functional characterization, such as with whole genome sequencing, are described. The role of transcriptomics, as well as resistome analysis, are also discussed. Furthermore, the manner in which all this work and knowledge could be incorporated into clinical endodontics in general, and regenerative endodontic therapy as a special treatment, is outlined. CONCLUSIONS: Comprehensive microbiome analysis can lead to the development of more effective and personalized antimicrobial treatment.

Endodontics↗

Gene identification signature (GIS) analysis for transcriptome characterization and genome annotation.

We have developed a DNA tag sequencing and mapping strategy called gene identification signature (GIS) analysis, in which 5' and 3' signatures of full-length cDNAs are accurately extracted into paired-end ditags (PETs) that are concatenated for efficient sequencing and mapped to genome sequences to demarcate the transcription boundaries of every gene. GIS analysis is potentially 30-fold more efficient than standard cDNA sequencing approaches for transcriptome characterization. We demonstrated this approach with 116,252 PET sequences derived from mouse embryonic stem cells. Initial analysis of this dataset identified hundreds of previously uncharacterized transcripts, including alternative transcripts of known genes. We also uncovered several intergenically spliced and unusual fusion transcripts, one of which was confirmed as a trans-splicing event and was differentially expressed. The concept of paired-end ditagging described here for transcriptome analysis can also be applied to whole-genome analysis of cis-regulatory and other DNA elements and represents an important technological advance for genome annotation.

5' Flanking Region↗

Transcript profiles of Nitrosomonas europaea during growth and upon deprivation of ammonia and carbonate.

The transcriptome of Nitrosomonas europaea was analyzed with whole-genome microarrays. Growing cells were compared to cells deprived of (NH4)2SO4 and Na2CO3. Hybridization signals were detected for 76% of the genes represented on the array under either or both conditions. Transcript levels for 68% of the genes were at least twofold higher in growing cells than in deprived cells, while only 0.42% of the genes were present at more than twofold higher levels in deprived cells. Transcript levels for the remaining 7% of the genes did not change significantly with the treatments. These trends were confirmed for selected genes by Northern hybridizations and quantitative RT-PCR. Compared to heterotrophic bacteria, N. europaea downregulates a greater proportion of its genes and fewer genes appear to be associated with the adaptation to starvation.

Ammonia↗

Transcriptional profiling in the adrenal gland reveals circadian regulation of hormone biosynthesis genes and nucleosome assembly genes.

The master circadian pacemaker of the suprachiasmatic nuclei coordinates behavioral and physiological rhythms via synchronization of subordinate peripheral oscillators in the central nervous system and organs throughout the body. Among these organs, the adrenal glands hold a prime position because of their regulatory influence on numerous physiological functions via rhythmic secretion of catecholamines and corticoid hormones into the bloodstream. In this report, the authors perform whole genome microarray hybridization to characterize the circadian transcriptome of the murine adrenal. They show that ~5% of the mouse genome is under circadian control in this gland. Using gene ontology analysis, they identify classes of transcripts that may synchronize adrenal hormone production. The authors' expression profiling also revealed that multiple histone genes implicated in either DNA replication or transcriptional regulation are clock controlled, suggesting a novel way by which the circadian clock may regulate the chromatin state.

Adrenal Glands↗

Composition and dynamics of the Caenorhabditis elegans early embryonic transcriptome.

Temporal profiles of transcript abundance during embryonic development were obtained by whole-genome expression analysis from precisely staged C. elegans embryos. The result is a highly resolved time course that commences with the zygote and extends into mid-gastrulation, spanning the transition from maternal to embryonic control of development and including the presumptive specification of most major cell fates. Transcripts for nearly half (8890) of the predicted open reading frames are detected and expression levels for the majority of them (>70%) change over time. The transcriptome is stable up to the four-cell stage where it begins rapidly changing until the rate of change plateaus before gastrulation. At gastrulation temporal patterns of maternal degradation and embryonic expression intersect indicating a mid-blastula transition from maternal to embryonic control of development. In addition, we find that embryonic genes tend to be expressed transiently on a time scale consistent with developmental decisions being made with each cell cycle. Furthermore, overall rates of synthesis and degradation are matched such that the transcriptome maintains a steady-state frequency distribution. Finally, a versatile analytical platform based on cluster analysis and developmental classification of genes is provided.

Animals↗

High MGMT expression identifies aggressive colorectal cancer with distinct genomic features and immune evasion properties.

INTRODUCTION: The epigenetic silencing of O6-methylguanine DNA methyltransferase (MGMT) is associated with reduced DNA repair capacity, carcinogenesis and increased sensitivity to alkylating chemotherapy. However, the biological role and clinical significance of MGMT overexpression in cancer remains poorly understood. METHODS: Using multiplexed quantitative immunofluorescence we measured the localized levels of MGMT protein, γH2AX and CD8+ T cells in multiple retrospective colorectal cancer (CRC) cohorts. Genomic and transcriptomic features of selected cases were also studied with whole exome DNA sequencing and genome-wide methylation analysis. MGMT-methylated human CRC cells SW620 were transfected with an MGMT-containing plasmid and co-cultured with allogeneic peripheral blood mononuclear cells. RESULTS: A subset of CRCs showed MGMT protein upregulation associated with lower γH2AX, reduced CD8+ tumor infiltrating lymphocytes (TILs), mismatch repair proficient (pMMR) status and shorter survival. CD8+ TILs were more distant from MGMT-expressing cells than MGMT-negative cells and the MGMT promoter methylation status did not highly correlate with MGMT protein levels in CRC. In genomic/transcriptomic analysis, high MGMT expression was associated with a lower nonsynonymous somatic mutational burden, higher transition-to-transversion mutation ratio, increased deleterious TP53 variants and distinct transcriptomic profiles. The exogenous expression of MGMT in SW620 CRC cells reduced the number of spontaneous nonsynonymous mutations, reproduced mutational features of MGMT-high CRC and limited the in vitro T-cell-mediated killing of malignant cells induced by proinflammatory cytokines in tumor/immune cell co-cultures. CONCLUSIONS: MGMT overexpression identifies a previously undescribed subset of CRCs with distinct biological and clinical properties including reduced mutagenesis, adaptive immune evasion, predominantly pMMR phenotype and aggressive clinical course. Direct, quantitative assessment of MGMT protein expression using spatially resolved analysis is more reliable than inference of MGMT expression by promoter methylation status in CRC.

Humans↗

Integrative spatial transcriptomic analysis pinpoints the role of the ferroxidase, TaMCO3, in wheat root tip iron mobilization.

Roots play a critical role in the sensing and absorption of essential minerals from the rhizosphere. Iron (Fe) deficiency, for example, triggers a well-known series of physiological and molecular responses within roots that facilitate uptake, which differs between monocots and dicots. In monocots, little is known about the molecular responses that occur within specific root development zones in response to iron deprivation, and how these differences result in overall nutrient uptake. Here, we conducted a transcriptome analysis of wheat root tips under Fe deficiency (-Fe) and performed a comparative transcriptome analysis with the previous datasets generated from the whole root. Gene ontology analysis of differentially expressed genes highlighted the significance of oxidoreductase activity and metal/ion transport in the root tip, which are critical for Fe mobilization. Interestingly, wheat, an allohexaploid species consisting of three different genomes (A, B, and D) displayed varying gene expression levels arising from the three genomes that contributed to similar molecular functions. Detailed analysis of oxidoreductase function at the root tip revealed multiple multicopper oxidase (MCO) proteins, such as Fe-responsive TaMCO3, that likely contribute to the overall ferroxidase activity. Further characterization of TaMCO3 shows that it complements the yeast FET3 mutant and rescues the -Fe sensitivity phenotype of Arabidopsis atmco3 mutants by enhancing vascular Fe loading. Transgenic wheat lines overexpressing TaMCO3 exhibited increased root Fe accumulation and improved tolerance to -Fe by augmenting the expression of Fe-mobilizing genes. Our findings highlight the role of spatially resolved gene expression in -Fe responses, suggesting strategies to reprogram cells for improved nutrient stress tolerance.

Triticum↗

Comparative genomics and adult-female transcriptomics prioritize physiological candidate pathways in the aquatic acentropine moth Paracymoriza distinctalis.

Freshwater-associated life histories are rare in Lepidoptera, and the physiological systems accompanying them remain poorly resolved. We integrated adult-female whole-body RNA-seq from Paracymoriza distinctalis (n = 3) and three terrestrial crambids (n = 3, 3, and 2) with focused comparative genomics to prioritize testable candidate pathways. Adult-female expression-biased genes were enriched for muscle contraction and myofibril assembly, carbohydrate and nucleotide-related metabolism, response to stimulus, and regulation of signal transduction. Protein-interaction analysis further identified coherent modules associated with RNA processing, carbon metabolism, the citrate cycle, and RAF/MAPK signaling. At the genome level, P. distinctalis retained broad macrosynteny with two crambid relatives, whereas putative lineage-biased genes were enriched for vitelline membrane formation, embryonic development, apoptosis, cytoskeletal organization, and transferase activity. Because the transcriptomes were obtained from whole adult females, these patterns may reflect locomotor, reproductive, metabolic, and tissue-composition differences and should not be interpreted as direct mechanisms of larval aquatic adaptation. Together, the results identify a concise set of adult-stage physiological candidates for stage-resolved, tissue-specific, and functional validation.

Acentropinae↗

Assessment of genomic prediction capabilities of transcriptome data in a barley multi-parent RIL population.

Low-cost and high-throughput RNA sequencing data for barley RILs achieved GP performance comparable to or better than traditional SNP array datasets when combined with parental whole-genome sequencing SNP data. The field of genomic selection (GS) is advancing rapidly on many fronts including the utilization of multi-omics datasets with the goal of increasing prediction ability and becoming an integral part of an increasing number of breeding programs ensuring future food security. In this study, we used RNA sequencing (RNA-Seq) data to perform genomic prediction (GP) on three related barley RIL populations. We investigated the potential of increasing prediction ability by combining genomic and transcriptomic datasets, adding whole-genome sequencing (WGS) SNP data, functional annotation-based filtering, and empirical quality filtering. Our RNA-Seq data were generated cost-efficiently using small-footprint plant cultivation, high-throughput RNA extraction, and Library preparation miniaturization. We also examined sequencing depth reduction as an additional cost-saving measure. We used fivefold cross-validation to evaluate the prediction ability of the gene expression dataset, the RNA-Seq SNP dataset, and the consensus SNP dataset between the RNA-Seq and parental WGS data, resulting in prediction abilities between 0.73 and 0.78. The consensus SNP dataset performed best, with five out of eight traits performing significantly better compared to a 50K SNP array, which served as a benchmark. The advantage of the consensus SNP dataset was most prominent in the inter-population predictions, in which the training and validation sets originated from different RIL sub-populations. We were therefore able to not only show that RNA-Seq data alone are able to predict various complex traits in barley using RILs, but also that the performance can be further increased with WGS data for which the public availability will steadily increase.

Hordeum↗

Transcriptional responses in mouse lungs induced by vaccination with Mycobacterium bovis BCG and infection with Mycobacterium tuberculosis.

Transcriptome analyses enable the assessment of signature alterations in whole tissues and organs undergoing pathological processes. We analyzed gene expression profiles of lungs from mice infected with Mycobacterium tuberculosis or vaccinated with Mycobacterium bovis bacille Calmette-Guérin (BCG). We compared high-dose systemic and low-dose aerosol M. tuberculosis infections as well as systemic BCG vaccination. Expression profiles in lungs were analyzed at day (d) 1 and d 30 post infection / vaccination using a custom tailored 'in situ' synthesized 60-mer oligonucleotide microarray with focus on immunologically relevant genes. At d 1, a small number of genes were differentially regulated, whereas at d 30, a discrete expression pattern was identified in the lung. Differential gene expression profiles between M. tuberculosis infection and BCG vaccination indicate differences in naturally and vaccine induced pulmonary immune responses. The shared signature of systemic and aerosol M. tuberculosis infection revealed dominance of genes related to or controlled by interferon gamma (IFN-gamma). We assume that differential gene expression profiles after M. tuberculosis infection are strongly influenced by differences in cellular composition of the lung due to migration of immune cells, primarily neutrophils, basophils, eosinophils and monocytes to the site of infection.

Animals↗

Intratumoral collagen correlates with histological grade and patient prognosis in breast cancer.

Histological grading, using the Nottingham Grading System (NGS), is a major prognostic indicator for breast cancer. NGS involves the scoring of cancer cell-related morphological features, yet it overlooks tumor microenvironment (TME) components such as collagen. Collagen proteins, integral to the extracellular matrix (ECM), influence tumor architecture and progression but their relationship with histological grade is not fully characterized. Here, we assessed intratumoral collagen deposition using Masson Trichrome staining of whole slides (n = 166), proteomic profiling (n = 2) and transcriptomic analyses of the METABRIC (n = 1827) and TCGA-BRCA (n = 753) cohorts. We showed that low-grade tumors display significantly higher intratumoral collagen deposition compared to high-grade tumors. Moreover, we demonstrated that collagen expression at the transcript and protein levels (Masson Trichrome) could discriminate Grade II carcinomas into distinct prognostic groups, in which patients with Grade II carcinomas with elevated levels of collagen expression were associated with lower pTNM stage and better survival outcomes. Our results support the inclusion of TME features, such as collagen deposition, to enhance prognostic accuracy in breast cancer.

Humans↗

Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes.

Epigenome-wide studies of pancreatic islets provide valuable insights into type 2 diabetes (T2D) but lack methylomes from individual cell types. Here we show changes to alpha and beta cell-specific methylomes and transcriptomes from people with or without T2D, using whole-genome bisulfite sequencing and RNA sequencing. We discover 22,544 differentially methylated regions annotated to 7,975 genes in alpha versus beta cells, such as INS, GCG, PDX1 and PCSK1, with ~50% showing differential expression. CRISPR-dCas9-DNMT3A-based epigenetic editing increases INS and TH DNA methylation, while CRISPR-dCas9-TET1-based editing decreases GCG methylation, each altering INS, TH or GCG expression and content in beta cells. Pre-T2D/T2D-associated differentially methylated regions in alpha and beta cells overlap 12-18% of T2D-associated genome-wide association study candidates. Additionally, ONECUT2 is epigenetically upregulated in beta cells from people with pre-T2D/T2D and elevated in male Goto-Kakizaki rat islets. ONECUT2 overexpression in beta cells/islets downregulates gene sets impacting insulin secretion and glucose homeostasis, and reduces mitochondrial activity, ATP/ADP ratio and insulin secretion. We also provide 'alpha-beta-methylome' ( https://alpha-beta-methylome.serve.scilifelab.se/app/alpha-beta-methylome/ ), a resource exploring T2D, age and sex associations on methylation, highlighting cell-specific epigenetic regulation and dysfunctions contributing to T2D.

Humans↗

Survey of conserved alternative splicing events of mRNAs encoding SR proteins in land plants.

The serine/arginine-rich (SR) protein family plays an important role in constitutive and alternative splicing (AS). These proteins regulate AS in a tissue-specific and stress-responsive manner. Pre-mRNAs encoding SR proteins are often alternatively spliced, and these AS events may be important for the regulation of AS events of other pre-mRNAs. In this study, we analyzed AS events of SR proteins in Arabidopsis thaliana and Oryza sativa (rice). We found three sets of AS events conserved between Arabidopsis and rice. These conserved AS events were found in the plant-novel-SR protein, SC35-like (SCL), and two-Zn-knuckles-type 9G8 subfamilies. Each member of these subfamilies has at least one RNA recognition motif (RRM) and at least one intron in the RRM-encoded region. We found that the conserved AS events occurred in these introns and, in each case, the conserved AS events resulted in mature mRNAs encoding proteins with incomplete RRMs. To search for the evolutionary origin of these AS events, we analyzed SR proteins in Physcomitrella patens (moss) in addition to those in Arabidopsis and rice. We found moss homologues of the plant-novel-SR protein, SCL, and the two-Zn-knuckles-type 9G8 subfamilies in silico, and these homologues have long introns at the same location of the conserved AS sites in Arabidopsis and rice. Such long introns are quite specific for alternatively spliced introns concerning the Arabidopsis SR protein genes. The long introns found in the moss SR protein genes strongly suggested that conserved AS events in moss SR protein genes might be similar to those in Arabidopsis and rice. We traced the evolutionary origin of the conserved AS events to 400 MYA, when plants first invaded land. These events are likely important in the regulation of whole AS events and likely contribute to the complicated transcriptome described by AS. The complicated transcriptome created by regulated AS events might have provided plants tolerance against droughts or temperature shifts and given them the ability to live on land.

Alternative Splicing↗

Chromosomal clustering of a human transcriptome reveals regulatory background.

BACKGROUND: There has been much evidence recently for a link between transcriptional regulation and chromosomal gene order, but the relationship between genomic organization, regulation and gene function in higher eukaryotes remains to be precisely defined. RESULTS: Here, we present evidence for organization of a large proportion of a human transcriptome into gene clusters throughout the genome, which are partly regulated by the same transcription factors, share biological functions and are characterized by non-housekeeping genes. This analysis was based on the cardiac transcriptome identified by our genome-wide array analysis of 55 human heart samples. We found 37% of these genes to be arranged mainly in adjacent pairs or triplets. A significant number of pairs of adjacent genes are putatively regulated by common transcription factors (p = 0.02). Furthermore, these gene pairs share a significant number of GO functional classification terms. We show that the human cardiac transcriptome is organized into many small clusters across the whole genome, rather than being concentrated in a few larger clusters. CONCLUSION: Our findings suggest that genes expressed in concert are organized in a linear arrangement for coordinated regulation. Determining the relationship between gene arrangement, regulation and nuclear organization as well as gene function will have broad biological implications.

Binding Sites↗

The rehydration transcriptome of the desiccation-tolerant bryophyte Tortula ruralis: transcript classification and analysis.

BACKGROUND: The cellular response of plants to water-deficits has both economic and evolutionary importance directly affecting plant productivity in agriculture and plant survival in the natural environment. Genes induced by water-deficit stress have been successfully enumerated in plants that are relatively sensitive to cellular dehydration, however we have little knowledge as to the adaptive role of these genes in establishing tolerance to water loss at the cellular level. Our approach to address this problem has been to investigate the genetic responses of plants that are capable of tolerating extremes of dehydration, in particular the desiccation-tolerant bryophyte, Tortula ruralis. To establish a sound basis for characterizing the Tortula genome in regards to desiccation tolerance, we analyzed 10,368 expressed sequence tags (ESTs) from rehydrated rapid-dried Tortula gametophytes, a stage previously determined to exhibit the maximum stress induced change in gene expression. RESULTS: The 10, 368 ESTs formed 5,563 EST clusters (contig groups representing individual genes) of which 3,321 (59.7%) exhibited similarity to genes present in the public databases and 2,242 were categorized as unknowns based on protein homology scores. The 3,321 clusters were classified by function using the Gene Ontology (GO) hierarchy and the KEGG database. The results indicate that the transcriptome contains a diverse population of transcripts that reflects, as expected, a period of metabolic upheaval in the gametophyte cells. Much of the emphasis within the transcriptome is centered on the protein synthetic machinery, ion and metabolite transport, and membrane biosynthesis and repair. Rehydrating gametophytes also have an abundance of transcripts that code for enzymes involved in oxidative stress metabolism and phosphorylating activities. The functional classifications reflect a remarkable consistency with what we have previously established with regards to the metabolic activities that are important in the recovery of the gametophytes from desiccation. A comparison of the GO distribution of Tortula clusters with an identical analysis of 9,981 clusters from the desiccation sensitive bryophyte species Physcomitrella patens, revealed, and accentuated, the differences between stressed and unstressed transcriptomes. Cross species sequence comparisons indicated that on the whole the Tortula clusters were more closely related to those from Physcomitrella than Arabidopsis (complete genome BLASTx comparison) although because of the differences in the databases there were more high scoring matches to the Arabidopsis sequences. The most abundant transcripts contained within the Tortula ESTs encode Late Embryogenesis Abundant (LEA) proteins that are normally associated with drying plant tissues. This suggests that LEAs may also play a role in recovery from desiccation when water is reintroduced into a dried tissue. CONCLUSION: The establishment of a rehydration EST collection for Tortula ruralis, an important plant model for plant stress responses and vegetative desiccation tolerance, is an important step in understanding the genome level response to cellular dehydration. The type of transcript analysis performed here has laid the foundation for more detailed functional and genome level analyses of the genes involved in desiccation tolerance in plants.

Arabidopsis↗

[Clinical proteomics in laboratory medicine].

During the past few years, the emphasis on genomics has shifted via transcriptomics to proteomics, the science of understanding how the whole set of proteins are expressed and function at the cellular level. Recent progress in clinical proteomics is mostly thanks to sophisticated new methodologies for proteome analyses. In search for novel biomarkers for cancers and other disorders, we have taken advantage of the surface-enhanced laser/desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS) and the MALDI-TOF/TOF. Since personal and verbal reporting of alcohol use is not necessarily accurate, objective markers to assess alcohol consumption are required. We used the ProteinChip SELDI technology to generate comparative protein profiles of the consecutive serum samples obtained during abstinence and found that a 5.9kD peptide detected and identified by this technology could be a novel marker of heavy alcohol consumption. Recent advances in two-dimensional electrophoresis (2-DE) such as fluorescent 2-D differential gel electrophoresis (2-D DIGE) has made it possible to detect and quantitate the critical changes involved in disease pathogenesis. We could identify novel proteins with altered expression in primary esophageal cancer using the powerful method of agarose 2-DE and agarose 2-D DIGE. A number of proteins with altered expression between cancer and adjacent non-cancer tissues were identified. Among them, a 195-kDa protein, periplakin, was significantly downregulated in esophageal cancer, which was confirmed by immunoblotting and immunohistochemistry. Clinical proteomics consists of the discovery proteomics and the measurement proteomics. Although we still stand at the discovery proteomics, undoubtedly, the clinical proteomics will be a major contributor in laboratory medicine in the near future.

Clinical Laboratory Techniques↗

Function-informed transcriptome analysis of Drosophila renal tubule.

BACKGROUND: Comprehensive, tissue-specific, microarray analysis is a potent tool for the identification of tightly defined expression patterns that might be missed in whole-organism scans. We applied such an analysis to Drosophila melanogaster Malpighian (renal) tubule, a defined differentiated tissue. RESULTS: The transcriptome of the D. melanogaster Malpighian tubule is highly reproducible and significantly different from that obtained from whole-organism arrays. More than 200 genes are more than 10-fold enriched and over 1,000 are significantly enriched. Of the top 200 genes, only 18 have previously been named, and only 45% have even estimates of function. In addition, 30 transcription factors, not previously implicated in tubule development, are shown to be enriched in adult tubule, and their expression patterns respect precisely the domains and cell types previously identified by enhancer trapping. Of Drosophila genes with close human disease homologs, 50 are enriched threefold or more, and eight enriched 10-fold or more, in tubule. Intriguingly, several of these diseases have human renal phenotypes, implying close conservation of renal function across 400 million years of divergent evolution. CONCLUSIONS: From those genes that are identifiable, a radically new view of the function of the tubule, emphasizing solute transport rather than fluid secretion, can be obtained. The results illustrate the phenotype gap: historically, the effort expended on a model organism has tended to concentrate on a relatively small set of processes, rather than on the spread of genes in the genome.

Animals↗

Transcriptome analysis of Shewanella oneidensis MR-1 in response to elevated salt conditions.

Whole-genomic expression patterns were examined in Shewanella oneidensis cells exposed to elevated sodium chloride. Genes involved in Na(+) extrusion and glutamate biosynthesis were significantly up-regulated, and the majority of chemotaxis/motility-related genes were significantly down-regulated. The data also suggested an important role for metabolic adjustment in salt stress adaptation in S. oneidensis.

Adaptation, Physiological↗