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Global transcriptional regulation of innate immunity by ATF-7 in C. elegans.

ABSTRACT: The nematode Caenorhabditis elegans has emerged as a genetically tractable animal host in which to study evolutionarily conserved mechanisms of innate immune signaling. We previously showed that the PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway regulates innate immunity of C. elegans through phosphorylation of the CREB/ATF bZIP transcription factor, ATF-7. Here, we have undertaken a genomic analysis of the transcriptional response of C. elegans to infection by Pseudomonas aeruginosa, combining genome-wide expression analysis by RNA-seq with ATF-7 chromatin immunoprecipitation followed by sequencing (ChIP-Seq). We observe that PMK-1-ATF-7 activity regulates a majority of all genes induced by pathogen infection, and observe ATF-7 occupancy in regulatory regions of pathogen-induced genes in a PMK-1-dependent manner. Moreover, functional analysis of a subset of these ATF-7-regulated pathogen-induced target genes supports a direct role for this transcriptional response in host defense. The genome-wide regulation through PMK-1- ATF-7 signaling reveals a striking level of control over the innate immune response to infection through a single transcriptional regulator.

SUBMITTER: Fletcher M

PROVIDER: S-EPMC6400416 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Global transcriptional regulation of innate immunity by ATF-7 in C. elegans.

Fletcher Marissa M Tillman Erik J EJ Butty Vincent L VL Levine Stuart S SS Kim Dennis H DH

PLoS genetics 20190221 2

The nematode Caenorhabditis elegans has emerged as a genetically tractable animal host in which to study evolutionarily conserved mechanisms of innate immune signaling. We previously showed that the PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway regulates innate immunity of C. elegans through phosphorylation of the CREB/ATF bZIP transcription factor, ATF-7. Here, we have undertaken a genomic analysis of the transcriptional response of C. elegans to infection by Pseudomonas aeruginosa, ...[more]

PMID: 30789901

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Project description:BackgroundBone morphogenetic proteins (BMPs) are members of the conserved transforming growth factor beta (TGFbeta superfamily, and play many developmental and homeostatic roles. In C. elegans, a BMP-like pathway, the DBL-1 pathway, controls body size and is involved in innate immunity. How these functions are carried out, though, and what most of the downstream targets of this pathway are, remain unknown.ResultsWe performed a microarray analysis and compared expression profiles of animals lacking the SMA-6 DBL-1 receptor, which decreases pathway signaling, with animals that overexpress DBL-1 ligand, which increases pathway signaling. Consistent with a role for DBL-1 in control of body size, we find positive regulation by DBL-1 of genes involved in physical structure, protein synthesis and degradation, and metabolism. However, cell cycle genes were mostly absent from our results. We also identified genes in a hedgehog-related pathway, which may comprise a secondary signaling pathway downstream of DBL-1 that controls body size. In addition, DBL-1 signaling up-regulates pro-innate immunity genes. We identified a reporter for DBL-1 signaling, which is normally repressed but is up-regulated when DBL-1 signaling is reduced.ConclusionsOur results indicate that body size in C. elegans is controlled in part by regulation of metabolic processes as well as protein synthesis and degradation. This supports the growing body of evidence that suggests cell size is linked to metabolism. Furthermore, this study discovered a possible role for hedgehog-related pathways in transmitting the BMP-like signal from the hypodermis, where the core DBL-1 pathway components are required, to other tissues in the animal. We also identified the up-regulation of genes involved in innate immunity, clarifying the role of DBL-1 in innate immunity. One of the highly regulated genes is expressed at very low levels in wild-type animals, but is strongly up-regulated in Sma/Mab mutants, making it a useful reporter for DBL-1/BMP-like signaling in C. elegans.

Dataset Information

Global transcriptional regulation of innate immunity by ATF-7 in C. elegans.

Publications

Global transcriptional regulation of innate immunity by ATF-7 in C. elegans.

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