Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Combining transcriptional profiling and genetic linkage analysis to uncover gene networks operating in hematopoietic stem cells and their progeny.

ABSTRACT: Stem cells are unique in that they possess both the capacity to self-renew and thereby maintain their original pool as well as the capacity to differentiate into mature cells. In the past number of years, transcriptional profiling of enriched stem cell populations has been extensively performed in an attempt to identify a universal stem cell gene expression signature. While stem-cell-specific transcripts were identified in each case, this approach has thus far been insufficient to identify a universal group of core "stemness" genes ultimately responsible for self-renewal and multipotency. Similarly, in the hematopoietic system, comparisons of transcriptional profiles between different hematopoietic cell stages have had limited success in revealing core genes ultimately responsible for the initiation of differentiation and lineage specification. Here, we propose that the combined use of transcriptional profiling and genetic linkage analysis, an approach called "genetical genomics", can be a valuable tool to assist in the identification of genes and gene networks that specify "stemness" and cell fate decisions. We review past studies of hematopoietic cells that utilized transcriptional profiling and/or genetic linkage analysis, and discuss several potential future applications of genetical genomics.

SUBMITTER: Gerrits A

PROVIDER: S-EPMC2493868 | biostudies-other | 2008 Aug

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Genetic networks of liver metabolism revealed by integration of metabolic and transcriptional profiling.

Project description:Although numerous quantitative trait loci (QTL) influencing disease-related phenotypes have been detected through gene mapping and positional cloning, identification of the individual gene(s) and molecular pathways leading to those phenotypes is often elusive. One way to improve understanding of genetic architecture is to classify phenotypes in greater depth by including transcriptional and metabolic profiling. In the current study, we have generated and analyzed mRNA expression and metabolic profiles in liver samples obtained in an F2 intercross between the diabetes-resistant C57BL/6 leptin(ob/ob) and the diabetes-susceptible BTBR leptin(ob/ob) mouse strains. This cross, which segregates for genotype and physiological traits, was previously used to identify several diabetes-related QTL. Our current investigation includes microarray analysis of over 40,000 probe sets, plus quantitative mass spectrometry-based measurements of sixty-seven intermediary metabolites in three different classes (amino acids, organic acids, and acyl-carnitines). We show that liver metabolites map to distinct genetic regions, thereby indicating that tissue metabolites are heritable. We also demonstrate that genomic analysis can be integrated with liver mRNA expression and metabolite profiling data to construct causal networks for control of specific metabolic processes in liver. As a proof of principle of the practical significance of this integrative approach, we illustrate the construction of a specific causal network that links gene expression and metabolic changes in the context of glutamate metabolism, and demonstrate its validity by showing that genes in the network respond to changes in glutamine and glutamate availability. Thus, the methods described here have the potential to reveal regulatory networks that contribute to chronic, complex, and highly prevalent diseases and conditions such as obesity and diabetes.

| S-EPMC2265422 | biostudies-literature

Combining QTL-seq and linkage mapping to uncover the genetic basis of single vs. paired spikelets in the advanced populations of two-ranked maize×teosinte.

Project description:BackgroundTeosinte ear bears single spikelet, whereas maize ear bears paired spikelets, doubling the number of grains in each cupulate during maize domestication. In the past 20 years, genetic analysis of single vs. paired spikelets (PEDS) has been stagnant. A better understanding of genetic basis of PEDS could help fine mapping of quantitative trait loci (QTL) and cloning of genes.ResultsIn this study, the advanced mapping populations (BC3F2 and BC4F2) of maize × teosinte were developed by phenotypic recurrent selection. Four genomic regions associated with PEDS were detected using QTL-seq, located on 194.64-299.52 Mb, 0-162.80 Mb, 12.82-97.17 Mb, and 125.06-157.01 Mb of chromosomes 1, 3, 6, and 8, respectively. Five QTL for PEDS were identified in the regions of QTL-seq using traditional QTL mapping. Each QTL explained 1.12-38.05% of the phenotypic variance (PVE); notably, QTL qPEDS3.1 with the average PVE of 35.29% was identified in all tests. Moreover, 14 epistatic QTL were detected, with the total PVE of 47.57-66.81% in each test. The QTL qPEDS3.1 overlapped with, or was close to, one locus of 7 epistatic QTL. Near-isogenic lines (NILs) of QTL qPEDS1.1, qPEDS3.1, qPEDS6.1, and qPEDS8.1 were constructed. All individuals of NIL-qPEDS6.1(MT1) and NIL-qPEDS8.1(MT1) showed paired spikelets (PEDS = 0), but the flowering time was 7 days shorter in the NIL-qPEDS8.1(MT1). The ratio of plants with PEDS > 0 was low (1/18 to 3/18) in the NIL-qPEDS1.1(MT1) and NIL-qPEDS3.1(MT1), maybe due to the epistatic effect.ConclusionOur results suggested that major QTL, minor QTL, epistasis and photoperiod were associated with the variation of PEDS, which help us better understand the genetic basis of PEDS and provide a genetic resource for fine mapping of QTL.

| S-EPMC8642974 | biostudies-literature

Combining biological networks to predict genetic interactions.

Project description:Genetic interactions define overlapping functions and compensatory pathways. In particular, synthetic sick or lethal (SSL) genetic interactions are important for understanding how an organism tolerates random mutation, i.e., genetic robustness. Comprehensive identification of SSL relationships remains far from complete in any organism, because mapping these networks is highly labor intensive. The ability to predict SSL interactions, however, could efficiently guide further SSL discovery. Toward this end, we predicted pairs of SSL genes in Saccharomyces cerevisiae by using probabilistic decision trees to integrate multiple types of data, including localization, mRNA expression, physical interaction, protein function, and characteristics of network topology. Experimental evidence demonstrated the reliability of this strategy, which, when extended to human SSL interactions, may prove valuable in discovering drug targets for cancer therapy and in identifying genes responsible for multigenic diseases.

| S-EPMC524818 | biostudies-literature

Diabetes Induces a Transcriptional Signature in Bone Marrow-Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction.

Project description:Hematopoietic stem/progenitor cells (HSPCs) participate in cardiovascular (CV) homeostasis and generate different types of blood cells including lymphoid and myeloid cells. Diabetes mellitus (DM) is characterized by chronic increase of pro-inflammatory mediators, which play an important role in the development of CV disease, and increased susceptibility to infections. Here, we aimed to evaluate the impact of DM on the transcriptional profile of HSPCs derived from bone marrow (BM). Total RNA of BM-derived CD34+ stem cells purified from sternal biopsies of patients undergoing coronary bypass surgery with or without DM (CAD and CAD-DM patients) was sequenced. The results evidenced 10566 expressed genes whose 79% were protein-coding genes, and 21% non-coding RNA. We identified 139 differentially expressed genes (p-value < 0.05 and |log2 FC| > 0.5) between the two comparing groups of CAD and CAD-DM patients. Gene Set Enrichment Analysis (GSEA), based on Gene Ontology biological processes (GO-BP) terms, led to the identification of fourteen overrepresented biological categories in CAD-DM samples. Most of the biological processes were related to lymphocyte activation, chemotaxis, peptidase activity, and innate immune response. Specifically, HSPCs from CAD-DM patients displayed reduced expression of genes coding for proteins regulating antibacterial and antivirus host defense as well as macrophage differentiation and lymphocyte emigration, proliferation, and differentiation. However, within the same biological processes, a consistent number of inflammatory genes coding for chemokines and cytokines were up-regulated. Our findings suggest that DM induces transcriptional alterations in HSPCs, which are potentially responsible of progeny dysfunction.

| S-EPMC7866997 | biostudies-literature

Genetic interactions among scribbler, Atrophin and groucho in Drosophila uncover links in transcriptional repression.

Project description:In eukaryotes, the ability of DNA-binding proteins to act as transcriptional repressors often requires that they recruit accessory proteins, known as corepressors, which provide the activity responsible for silencing transcription. Several of these factors have been identified, including the Groucho (Gro) and Atrophin (Atro) proteins in Drosophila. Here we demonstrate strong genetic interactions between gro and Atro and also with mutations in a third gene, scribbler (sbb), which encodes a nuclear protein of unknown function. We show that mutations in Atro and Sbb have similar phenotypes, including upregulation of the same genes in imaginal discs, which suggests that Sbb cooperates with Atro to provide repressive activity. Comparison of gro and Atro/sbb mutant phenotypes suggests that they do not function together, but instead that they may interact with the same transcription factors, including Engrailed and C15, to provide these proteins with maximal repressive activity.

| S-EPMC1526535 | biostudies-literature

Regulation of hematopoietic stem cells by their mature progeny.

Project description:Thrombopoietin (TPO), acting through its receptor Mpl, has two major physiological roles: ensuring production of sufficient platelets via stimulation of megakaryocyte production and maintaining hematopoietic stem cell (HSC) quiescence. Mpl also controls circulating TPO concentration via receptor-mediated internalization and degradation. Here, we demonstrate that the megakaryocytosis and increased platelet mass in mice with mutations in the Myb or p300 genes causes reduced circulating TPO concentration and TPO starvation of the stem-cell compartment, which is exacerbated because these cells additionally exhibit impaired responsiveness to TPO. HSCs from Myb(Plt4/Plt4) mice show altered expression of TPO-responsive genes and, like HSCs from Tpo and Mpl mutant mice, exhibit increased cycling and a decline in the number of HSCs with age. These studies suggest that disorders of platelet number can have profound effects on the HSC compartment via effects on the feedback regulation of circulating TPO concentration.

| S-EPMC3003054 | biostudies-literature

Transcriptional profiling of Foxo3a and Fancd2 regulated genes in mouse hematopoietic stem cells.

Project description:Functional maintenance of hematopoietic stem cells (HSCs) is constantly challenged by stresses like DNA damage and oxidative stress. Foxo factors, particularly Foxo3a, function to regulate the self-renewal of HSCs and contribute to the maintenance of the HSC pool during aging by providing resistance to oxidative stress. Fancd2-deficient mice had multiple hematopoietic defects, including HSC loss in early development and in response to cellular stresses including oxidative stress. The cellular mechanisms underlying HSC loss in Fancd2-deficient mice include abnormal cell cycle status, loss of quiescence, and compromised hematopoietic repopulating capacity of HSCs. To address on a genome wide level the genes and pathways that are impacted by deletion of the Fancd2 and Foxo3a, we performed microarray analysis on phenotypic HSCs (Lin-ckit+Sca-1+CD150+CD48-) from Fancd2 single knockout, Foxo3a single knockout and Fancd2-/-Foxo3a-/- double-knockout (dKO) mice. Here we provide detailed methods and analysis on these microarray data which has been deposited in Gene Expression Omnibus (GEO): GSE64215.

| S-EPMC4430722 | biostudies-literature

Versatile RNA-sensing transcriptional regulators for engineering genetic networks.

Project description:The widespread natural ability of RNA to sense small molecules and regulate genes has become an important tool for synthetic biology in applications as diverse as environmental sensing and metabolic engineering. Previous work in RNA synthetic biology has engineered RNA mechanisms that independently regulate multiple targets and integrate regulatory signals. However, intracellular regulatory networks built with these systems have required proteins to propagate regulatory signals. In this work, we remove this requirement and expand the RNA synthetic biology toolkit by engineering three unique features of the plasmid pT181 antisense-RNA-mediated transcription attenuation mechanism. First, because the antisense RNA mechanism relies on RNA-RNA interactions, we show how the specificity of the natural system can be engineered to create variants that independently regulate multiple targets in the same cell. Second, because the pT181 mechanism controls transcription, we show how independently acting variants can be configured in tandem to integrate regulatory signals and perform genetic logic. Finally, because both the input and output of the attenuator is RNA, we show how these variants can be configured to directly propagate RNA regulatory signals by constructing an RNA-meditated transcriptional cascade. The combination of these three features within a single RNA-based regulatory mechanism has the potential to simplify the design and construction of genetic networks by directly propagating signals as RNA molecules.

| S-EPMC3102349 | biostudies-literature

How Gene Networks Can Uncover Novel CVD Players.

Project description:Cardiovascular diseases (CVD) are complex, involving numerous biological entities from genes and small molecules to organ function. Placing these entities in networks where the functional relationships among the constituents are drawn can aid in our understanding of disease onset, progression and prevention. While networks, or interactomes, are often classified by a general term, say lipids or inflammation, it is a more encompassing class of network that is more informative in showing connections among the active entities and allowing better hypotheses of novel CVD players to be formulated. A range of networks will be presented whereby the potential to bring new objects into the CVD milieu will be exemplified.

| S-EPMC3966201 | biostudies-literature

T Cell Transcriptional Profiling and Immunophenotyping Uncover LAG3 as a Potential Significant Target of Immune Modulation in Multiple Myeloma.

Project description:Autologous stem cell transplant (ASCT) is the standard of care for patients with multiple myeloma (MM). The clinical significance of peripheral blood T lymphocyte (PBTL) immunologic changes associated with ASCT is poorly understood. Here we evaluated T cell transcriptional messenger RNA profiles and immunophenotypes to correlate immunologic senescence, exhaustion, and anergy with clinical endpoints in a cohort of patients with MM undergoing ASCT. ASCT induced global transcriptional T cell changes and altered molecular levels of markers of T cell subtypes, T cell activation, and exhaustion. These included reduced CD4/CD8 ratio, skewing toward the Th1 subset, reduced expression of costimulatory receptors CD27 and CD28, heightened T cell activation, and increased expression of immune modulatory molecules LAG3 and PD1. Multicolor flow cytometry experiments confirmed altered circulating CD4 and CD8 subsets and skewing toward differentiated effector cells. Moreover, ASCT promoted an exhausted immunophenotype in CD3+CD4+ subsets and a senescent immunophenotype in CD3+CD8+ subsets. Subset-specific altered expression was also seen for surface molecules with immunomodulatory function. ASCT affected soluble levels of molecules with immunomodulatory function by increasing plasma HVEM and TIM3. High molecular LAG3 level was associated with inferior event-free survival post-ASCT (hazard ratio = 5.44; confidence interval, 1.92 to 15.46; P = .001; adjusted P [controlling for false discovery rate] = .038). Using a comprehensive evaluation of PBTLs on a molecular and phenotypic level, we have identified that ASCT induces global T cell alterations with CD4 and CD8 subset-specific changes. Moreover, LAG3 emerged as an early biomarker of adverse events post-ASCT. These findings will support the development of treatment strategies targeting immune defects in MM to augment or restore T cell responses.

| S-EPMC6952061 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data