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Quantitating transcription factor redundancy: The relative roles of the ELT-2 and ELT-7 GATA factors in the C. elegans endoderm

ABSTRACT: Two GATA transcription factors, ELT-2 and ELT-7, function in the differentiation of the Caenorhabditis elegans intestine. Though loss of elt-7 causes no discernable phenotype on its own, it significantly enhances intestinal morphology defects in elt-2 loss-of-function mutants. We sought to identify the cohorts of gene targets unique to or shared by ELT-2 and ELT-7 in an effort to determine the logic underlying their differential impact on intestinal development.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE107175 | GEO | 2018/02/22

REPOSITORIES: GEO

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Project description:In the past decade, the paradigm which claimed that invertebrate immune systems lack specificity has been reconsidered. Accumulating evidence supports that invertebrate immune systems are able to mount specific responses to the pathogen species-, and even to the pathogen strain-level. However, the underlying molecular mechanisms behind invertebrate immune specificity remain mostly unknown. Studying the molecular basis of invertebrate immune specificity in a genetically tractable model, such as the nematode Caenorhabditis elegans, has the potential to reveal insights into the immune systems of other metazoans, including humans. We chose to study the mechanisms of specific immune responses of the worm to two different pathogenic strains of the Gram-positive bacterium Bacillus thuringiensis (MYBY18247 and MYBT18679), because there is phenotypic evidence of specific genotype-genotype interactions between this host-pathogen pair. We did an initial RNA-Seq experiment upon pathogen exposure and found that 9% of the differentially expressed genes change their expression in different ways when comparing the two pathogen strains. Through promoter region motif enrichment analysis, we found the GATA transcription factor ELT-2 is responsible for the pathogen strain-specific transcriptomic response. Upon elt-2 knockdown worms exposed to MYBT18679 display lower survival rate coupled with higher intestinal damage than non-infected controls. Additionally, by performing further genetic analysis using gene knockdown and knockout, we found that the p38 MAPK pathway acts likely in parallel to elt-2 and the transcription factor skn-1 cooperates with elt-2 to promote resistance to MYBT18679. On the other hand, elt-2 knockdown leads to a substantially higher survival rate, together with lower intestinal tissue damage compared to control worms, upon exposure to MYBT18247, another pathogenic Bacillus thuringiensis strain. The MYBT18247 pathogen load of elt-2(RNAi) worms compared to control worms remained unchanged, suggesting the elt-2 negatively regulates tolerance towards MYBT18247. We found that tolerance to MYBT18247 was positively regulated by the transcription factors: FOXO daf-16, bZip zip-2, nhr-99 and nhr-193. To identify elt-2 negatively-regulated downstream targets that could promote tolerance to MYBT18247, we performed a second RNA-Seq experiment, this time including elt-2(RNAi) worms exposed to both pathogenic strains. We found four genes negatively regulated by elt-2: cdr-2, poml-3, dhs-30 and tre-3, with putative function in detoxification and lipid metabolism, which can mediate tolerance to MYBT18247. We conclude that ELT-2 coordinates strain-specific immune responses in this invertebrate host and promotes resistance upon exposure to MYBT18679, while it negatively regulates tolerance to MYBT18247. The response is likely to be specific to the crystal pore-forming toxins produced by this pathogen.

Project description:modENCODE_submission_2614 This submission comes from a modENCODE project of Michael Snyder. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: We are identifying the DNA binding sites for 300 transcription factors in C. elegans. Each transcription factor gene is tagged with the same GFP fusion protein, permitting validation of the gene's correct spatio-temporal expression pattern in transgenic animals. Chromatin immunoprecipitation on each strain is peformed using an anti-GFP antibody, and any bound DNA is deep-sequenced using Solexa GA2 technology. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf EXPERIMENT TYPE: CHIP-seq. BIOLOGICAL SOURCE: Strain: OP75(made_by : R Waterston description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The ELT-3::EGFP fusion protein is expressed in the correct elt-3 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the ELT-3 transcription factor. tags : GFP::3xFlag mutagen : Bombard outcross : 3 genotype : unc-119 (ed3) III; wgIs75 [elt-3::TY1::EGFP::FLAG; unc-119 (+)] official name : OP75 ); Developmental Stage: fed L1; Genotype: unc-119 (ed3) III; wgIs75 [elt-3::TY1::EGFP::FLAG; unc-119 (+)]; Sex: Hermaphrodite; EXPERIMENTAL FACTORS: Developmental Stage fed L1; Target gene elt-3; Strain OP75(made_by : R Waterston description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The ELT-3::EGFP fusion protein is expressed in the correct elt-3 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the ELT-3 transcription factor. tags : GFP::3xFlag mutagen : Bombard outcross : 3 genotype : unc-119 (ed3) III; wgIs75 [elt-3::TY1::EGFP::FLAG; unc-119 (+)] official name : OP75 ); temp (temperature) 20 degree celsius Series_type: CHIP-seq

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Quantitating transcription factor redundancy: The relative roles of the ELT-2 and ELT-7 GATA factors in the C. elegans endoderm

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