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Caenorhabditis elegans
12 Downloadable Samples
Affymetrix C. elegans Genome Array (celegans)
Description
The roundworm Caenorhabditis elegans is a heme auxotroph that requires the coordinated actions of HRG-1 heme permeases to transport environmental heme into the intestine and HRG-3, a secreted protein, to deliver intestinal heme to other tissues including the embryo. Here we show that heme homeostasis in the extraintestinal hypodermal tissue is facilitated by the transmembrane protein HRG-2. Systemic heme deficiency upregulates hrg-2 mRNA expression over 200-fold in the main body hypodermal syncytium hyp 7. HRG-2 is a type I membrane protein which binds heme and localizes to the endoplasmic reticulum and apical plasma membrane. Cytochrome heme profiles are aberrant in HRG-2 deficient worms, a phenotype that is partially suppressed by heme supplementation. Heme-deficient yeast strain, ectopically expressing worm HRG-2, reveal significantly improved growth at submicromolar concentrations of exogenous heme. Taken together, our results implicate HRG-2 as a facilitator of heme utilization in the C. elegans hypodermis and provide a mechanism for regulation of heme homeostasis in an extraintestinal tissue.
Publication Title
Heme utilization in the Caenorhabditis elegans hypodermal cells is facilitated by heme-responsive gene-2.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 22 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
DNA Methylation Changes in Lung Immune Cells Are Associated with Granulomatous Lung Disease.
Sample Metadata Fields
Sex, Age, Treatment, Race
View Samples- Homo sapiens
- 22 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The goal of this study was to investigate and correlate differential methylation and expression in cells from the target organ in non-infectious granulomatous lung diseases, specifically sarcoidosis and chronic beryllium disease (CBD). To that end, cells were collected from patients via bronchoalveolar lavage (BAL), and extracted nucleic acids were hybridized to genome-wide arrays.
Publication Title
DNA Methylation Changes in Lung Immune Cells Are Associated with Granulomatous Lung Disease.
Sample Metadata Fields
Sex, Age, Treatment, Race
View Samples- Caenorhabditis elegans
- 20 Downloadable Samples
Illumina HiSeq 2500
Description
Purpose: The goal of this study is to understand how dbl-1, which is made primarily in neurons, and hrg-7, which is exclusively made in the intestine, contribute to systemic heme homeostasis. Methods: mRNA profiles of late L4 dbl-1(nk3) and hrg-7(tm6801) mutant C. elegans fed OP50 E. coli or OP50 + 50µM heme were compared to mRNA profiles from wildtype (WT) broodmates. Profiles were generated with single-end 50 base reads obtained using Illumina’s HiSeq 2500. Bioinformatics quality control was performed followed by alignment of reads to the ce10 reference genome using Tophat2, version 2.1.0. We found differentially expressed genes using Cufflinks 2, version 2.2.1 with a cutoff of 0.05 on False Discovery Rate (FDR). Results: We found a substantial overlap of genes regulated by both dbl-1 and hrg-7, including 49 heme-responsive genes (hrgs) in low heme (OP50) and 11 hrgs in high heme (OP50 + 50µM). Additionally, our data indicate crosstalk between dbl-1 and hrg-7 signaling. dbl-1 directly regulates hrg-7 expression, while hrg-7 regulates three components of the dbl-1 signaling pathway. Conclusions: Our study demonstrates that communication between the neuron and intestine is essential for heme homeostasis. Specifically, we report that HRG-7 functions as a secreted signaling factor which communicates intestinal heme status with extraintestinal tissues by integrating a DBL-1/BMP -dependent response from the neurons to transcriptionally regulate genes involved in heme homeostasis. Cellular requirements for heme are fulfilled by a cell’s internal capacity to synthesize its own heme in a cell-autonomous manner. However, growing evidence in vertebrates predicts that cellular heme levels in animals are not only maintained by heme synthesis, but also by distally located proteins that could signal systemic heme requirements to an inter-organ heme trafficking network through cell-nonautonomous regulation. Using C. elegans, a genetically and optically amenable animal model for visualizing heme-dependent signaling, we show that HRG-7, an aspartic protease homolog, mediates inter-organ signaling between the intestine and neuron. Loss of hrg-7 results in robust expression of intestinal heme importers and, remarkably, this occurs even under heme replete conditions when such transporters are not normally expressed. HRG-7 functions as a secreted signaling factor, independent of a functional enzymatic active site, and communicates intestinal heme status with extraintestinal tissues by integrating a DBL-1/BMP -dependent response from the neurons to transcriptionally regulate intestinal heme homeostasis. Given the evidence indicating that mechanisms of heme transport are conserved across metazoa, it is conceivable that the cell-nonautonomous signaling framework that we uncovered in C. elegans may have functional relevance for inter-organ regulation of iron and heme metabolism in humans. Overall design: Comparison of mRNA profiles from dbl-1(nk3) mutant C. elegans vs. wildtype (WT) broodmates and hrg-7(tm6801) mutants vs (WT) broomates fed OP50 E. coli or OP50 + 50µM heme. Biological duplicates were analyzed for dbl-1(nk3) mutants and (WT) broodmates. Biological triplicates were analyzed for hrg-7(tm6801) mutants and (WT) broodmates.
Publication Title
Inter-organ signalling by HRG-7 promotes systemic haem homeostasis.
Sample Metadata Fields
Cell line, Subject
View Samples- Caenorhabditis elegans
- 9 Downloadable Samples
- Affymetrix C. elegans Genome Array (celegans)
Description
Hemes are essential but potentially cytotoxic cofactors that participate in critical and diverse biological processes. Although the pathway and intermediates for heme biosynthesis have been well defined, the intracellular networks which mediate heme trafficking remain unknown. Caenorhabditis elegans and related helminths are natural heme auxotrophs requiring environmental heme for growth and development. We exploited this auxotrophy to identify HRG-1 and HRG-4 in C. elegans and show that they are essential for heme homeostasis and normal vertebrate development. We demonstrate that heme deficiency upregulates expression of hrg-4 and its evolutionarily conserved paralog hrg-1. Depletion of either HRG-1 or HRG-4 in worms results in disruption of organismal heme sensing and abnormal response to heme analogs. HRG-1 and HRG-4 are novel transmembrane proteins that bind heme and have evolutionarily conserved functions. Transient knockdown of hrg-1 in zebrafish leads to hydrocephalus, yolk tube malformations, and, most strikingly, profound defects in erythropoiesis - phenotypes that are fully rescued by worm HRG-1. These findings reveal unanticipated and conserved pathways for cellular heme trafficking in animals that defines the paradigm for eukaryotic heme transport. Uncovering the mechanisms of heme transport in C. elegans will provide novel insights into human disorders of heme metabolism and generate unique anthelmintics to combat worm infestations.
Publication Title
Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins.
Sample Metadata Fields
No sample metadata fields
View Samples- Drosophila melanogaster
- 10 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Cigarette smoking is associated with reduced risk of developing Parkinsons disease (PD). To identify genes that interact with nicotine/smoking, we performed hypothesis-free genome-wide experiments in a paraquat-induced Drosophila model and in a case-control study of PD. We demonstrated that nicotine extends life-span in paraquat-treated Drosophila (P=4E-30). Brain tissue from flies treated with combinations of paraquat and nicotine revealed elevated expression of CG14691 with paraquat which was restored with nicotine co-treatment (P(interaction)=2E-11, P(FDR-adjusted)=4E-7). Independently, variants in the 5 region of SV2C, a human ortholog of CG14691, gave the strongest signal for interaction with smoking (P(interaction)=9E-8). The effect of smoking on PD risk varied six-fold by SV2C genotype (P(heterogeneity)=4E-10). Moreover, SV2C variants identified here were associated with SVC2 gene-expression in the HapMap data. Present results suggest synaptic vesicle protein SV2C plays a role in PD pathogenesis, and that the SV2C genotype may be useful for clinical trials of nicotine for treating PD.
Publication Title
A genetic basis for the variable effect of smoking/nicotine on Parkinson's disease.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 52 Downloadable Samples
- Illumina HumanRef-8 v3.0 expression beadchip, Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 21 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2), Affymetrix Murine Genome U74A Array (mgu74a)
Description
Comparison of laminin binding and laminin non-binding germ cells
Publication Title
Defining the spermatogonial stem cell.
Sample Metadata Fields
No sample metadata fields
View Samples
GSE830- Rattus norvegicus
- 18 Downloadable Samples
- Affymetrix Rat Expression 230A Array (rae230a)
Description
Rat germ cells
Publication Title
Defining the spermatogonial stem cell.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Analysis of the influence of celiac disease-associated bacteria and gluten on intestinal epithelial cells
Publication Title
Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells.
Sample Metadata Fields
Cell line, Treatment
View Samples