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Genome-wide analysis reveals novel genes essential for heme homeostasis in Caenorhabditis elegans
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نویسنده
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severance s. ,rajagopal a. ,rao a.u. ,cerqueira g.c. ,mitreva m. ,el-sayed n.m. ,krause m. ,hamza i.
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منبع
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plos genetics - 2010 - دوره : 6 - شماره : 7 - صفحه:1 -16
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چکیده
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Heme is a cofactor in proteins that function in almost all sub-cellular compartments and in many diverse biological processes. heme is produced by a conserved biosynthetic pathway that is highly regulated to prevent the accumulation of heme-a cytotoxic,hydrophobic tetrapyrrole. caenorhabditis elegans and related parasitic nematodes do not synthesize heme,but instead require environmental heme to grow and develop. heme homeostasis in these auxotrophs is,therefore,regulated in accordance with available dietary heme. we have capitalized on this auxotrophy in c. elegans to study gene expression changes associated with precisely controlled dietary heme concentrations. rna was isolated from cultures containing 4,20,or 500 μm heme; derived cdna probes were hybridized to affymetrix c. elegans expression arrays. we identified 288 heme-responsive genes (hrgs) that were differentially expressed under these conditions. of these genes,42% had putative homologs in humans,while genomes of medically relevant heme auxotrophs revealed homologs for 12% in both trypanosoma and leishmania and 24% in parasitic nematodes. depletion of each of the 288 hrgs by rna-mediated interference (rnai) in a transgenic heme-sensor worm strain identified six genes that regulated heme homeostasis. in addition,seven membrane-spanning transporters involved in heme uptake were identified by rnai knockdown studies using a toxic heme analog. comparison of genes that were positive in both of the rnai screens resulted in the identification of three genes in common that were vital for organismal heme homeostasis in c. elegans. collectively,our results provide a catalog of genes that are essential for metazoan heme homeostasis and demonstrate the power of c. elegans as a genetic animal model to dissect the regulatory circuits which mediate heme trafficking in both vertebrate hosts and their parasites,which depend on environmental heme for survival.
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آدرس
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department of animal and avian sciences,university of maryland,college park,md,united states,department of cell biology and molecular genetics,university of maryland,college park,md, United States, department of animal and avian sciences,university of maryland,college park,md,united states,department of cell biology and molecular genetics,university of maryland,college park,md, United States, department of animal and avian sciences,university of maryland,college park,md,united states,department of cell biology and molecular genetics,university of maryland,college park,md, United States, department of cell biology and molecular genetics,university of maryland,college park,md,united states,center for bioinformatics and computational biology,university of maryland,college park,md, United States, the genome center,department of genetics,washington university school of medicine,st. louis,mo, United States, department of cell biology and molecular genetics,university of maryland,college park,md,united states,center for bioinformatics and computational biology,university of maryland,college park,md, United States, laboratory of molecular biology,national institute of diabetes and digestive and kidney diseases,national institutes of health,bethesda,md, United States, department of animal and avian sciences,university of maryland,college park,md,united states,department of cell biology and molecular genetics,university of maryland,college park,md, United States
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Authors
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