Chen C et al. (2017) Nature "IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses."

Sheng M, Chen C, Laurent P, Itakura E, Nelson GM, Fenk LA, De Bono M, Hegde RS, Butcher RA

[Nature, 2017]

Interleukin-17 (IL-17) is a major pro-inflammatory cytokine: it mediates responses to pathogens or tissue damage, and drives autoimmune diseases. Little is known about its role in the nervous system. Here we show that IL-17 has neuromodulator-like properties in Caenorhabditis elegans. IL-17 can act directly on neurons to alter their response properties and contribution to behaviour. Using unbiased genetic screens, we delineate an IL-17 signalling pathway and show that it acts in the RMG hub interneurons. Disrupting IL-17 signalling reduces RMG responsiveness to input from oxygen sensors, and renders sustained escape from 21% oxygen transient and contingent on additional stimuli. Over-activating IL-17 receptors abnormally heightens responses to 21% oxygen in RMG neurons and whole animals. IL-17 deficiency can be bypassed by optogenetic stimulation of RMG. Inducing IL-17 expression in adults can rescue mutant defects within 6h. These findings reveal a non-immunological role of IL-17 modulating circuit function and behaviour.

Chen C et al. (2019) Nat Prod Res "Anti-aging derivatives of cycloastragenol produced by biotransformation."

Yan S, Chen G, Xu B, Huang H, Jiang B, Ni Y, Chen C, Fan B

[Nat Prod Res, 2019]

In this study, the microbial transformation of cycloastragenol (CA) by the fungi <i>Mucor subtilissimus</i> AS 3.2456 and <i>Aspergillus oryzae</i> AS 3.407 yielded 19 metabolites. Their structures were established based on extensive NMR and HR-MS data analyses, and six of them are new compounds. The two fungal strains exhibited distinct biocatalytic features. <i>M. subtilissimus</i> could catalyse hydroxylation and carbonylation reactions meanwhile the fragile 9,19-cyclopropane ring remained intact. <i>A. oryzae</i> preferred to catalyse hydroxylation, acetylation and ring expansion reactions. These highly specific reactions are difficult to achieve by chemical synthesis, particularly under mild conditions. Furthermore, we found that most of the metabolites could significantly extend the lifespan of <i>Caenorhabditis elegans</i> at 50M. These biotransformed derivatives of CA could be potential anti-aging agents.

Chen C et al. (2013) Nucleic Acids Res "Efficient genome editing in Caenorhabditis elegans by CRISPR-targeted homologous recombination."

De Bono M, Fenk LA, Chen C

[Nucleic Acids Res, 2013]

Cas9 is an RNA-guided double-stranded DNA nuclease that participates in clustered regularly interspaced short palindromic repeats (CRISPR)-mediated adaptive immunity in prokaryotes. CRISPR-Cas9 has recently been used to generate insertion and deletion mutations in Caenorhabditis elegans, but not to create tailored changes (knock-ins). We show that the CRISPR-CRISPR-associated (Cas) system can be adapted for efficient and precise editing of the C. elegans genome. The targeted double-strand breaks generated by CRISPR are substrates for transgene-instructed gene conversion. This allows customized changes in the C. elegans genome by homologous recombination: sequences contained in the repair template (the transgene) are copied by gene conversion into the genome. The possibility to edit the C. elegans genome at selected locations will facilitate the systematic study of gene function in this widely used model organism.

Chen C et al. (2007) BMC Syst Biol "A search engine to identify pathway genes from expression data on multiple organisms."

Weirauch MT, Zambon AC, Chen C, Powell CC, Stuart JM

[BMC Syst Biol, 2007]

ABSTRACT: BACKGROUND: The completion of several genome projects showed that most genes have not yet been characterized, especially in multicellular organisms. Although most genes have unknown functions, a large collection of data is available describing their transcriptional activities under many different experimental conditions. In many cases, the coregulatation of a set of genes across a set of conditions can be used to infer roles for genes of unknown function. RESULTS: We developed a search engine, the Multiple-Species Gene Recommender (MSGR), which scans gene expression datasets from multiple organisms to identify genes that participate in a genetic pathway. The MSGR takes a query consisting of a list of genes that function together in a genetic pathway from one of six organisms: Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, Arabidopsis thaliana, and Helicobacter pylori. Using a probabilistic method to merge searches, the MSGR identifies genes that are significantly coregulated with the query genes in one or more of those organisms. The MSGR achieves its highest accuracy for many human pathways when searches are combined across species. We describe specific examples in which new genes were identified to be involved in a neuromuscular signaling pathway and a cell-adhesion pathway. CONCLUSIONS: The search engine can scan large collections of gene expression data for new genes that are significantly coregulated with a pathway of interest. By integrating searches across organisms, the MSGR can identify pathway members whose coregulation is either ancient or newly evolved.

Chen C et al. (2012) J Biol Chem "Heme utilization in the Caenorhabditis elegans hypodermal cells is facilitated by heme-responsive gene-2."

Samuel TK, Krause M, Dailey HA, Chen C, Hamza I

[J Biol Chem, 2012]

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 was facilitated by the transmembrane protein HRG-2. Systemic heme deficiency up-regulated hrg-2 mRNA expression over 200-fold in the main body hypodermal syncytium, hyp 7. HRG-2 is a type I membrane protein that 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 was partially suppressed by heme supplementation. A heme-deficient yeast strain, ectopically expressing worm HRG-2, revealed significantly improved growth at submicromolar concentrations of exogenous heme. Taken together, our results implicate HRG-2 as a facilitator of heme utilization in the Caenorhabditis elegans hypodermis and provide a mechanism for the regulation of heme homeostasis in an extraintestinal tissue.

Chen C et al. (2009) PLoS Genet "Defects in tRNA modification associated with neurological and developmental dysfunctions in Caenorhabditis elegans elongator mutants."

Chen C, Tuck S, Bystrom AS

[PLoS Genet, 2009]

Elongator is a six subunit protein complex, conserved from yeast to humans. Mutations in the human Elongator homologue, hELP1, are associated with the neurological disease familial dysautonomia. However, how Elongator functions in metazoans, and how the human mutations affect neural functions is incompletely understood. Here we show that in Caenorhabditis elegans, ELPC-1 and ELPC-3, components of the Elongator complex, are required for the formation of the 5-carbamoylmethyl and 5-methylcarboxymethyl side chains of wobble uridines in tRNA. The lack of these modifications leads to defects in translation in C. elegans. ELPC-1::GFP and ELPC-3::GFP reporters are strongly expressed in a subset of chemosensory neurons required for salt chemotaxis learning. elpc-1 or elpc-3 gene inactivation causes a defect in this process, associated with a posttranscriptional reduction of neuropeptide and a decreased accumulation of acetylcholine in the synaptic cleft. elpc-1 and elpc-3 mutations are synthetic lethal together with those in tuc-1, which is required for thiolation of tRNAs having the 5'methylcarboxymethyl side chain. elpc-1; tuc-1 and elpc-3; tuc-1 double mutants display developmental defects. Our results suggest that, by its effect on tRNA modification, Elongator promotes both neural function and development.

Chen C et al. (2023) Molecules "High-Dose Deltamethrin Induces Developmental Toxicity in Caenorhabditis elegans via IRE-1."

Wang S, Deng Y, Zou Z, Chen C, Chen Z, Jin C, Liu L

[Molecules, 2023]

Deltamethrin (DM), a Type II pyrethroid, is widely used worldwide in agriculture, household applications, and medicine. Recent studies have shown that DM exerts a variety of toxic effects on organs such as the kidney, heart muscle, and nerves in animals. However, little is known about the effects of high-dose DM on growth and development, and the mechanism of toxicity remains unclear. Using the <i>Caenorhabditis elegans</i> model, we found that high-dose DM caused a delay in nematode development. Our results showed that high-dose DM reduced the activation of the endoplasmic reticulum unfolded protein response (UPR^ER). Further studies revealed that high-dose DM-induced developmental toxicity and reduced capacity for UPR^ER activation were associated with the IRE-1/XBP-1 pathway. Our results provide new evidence for the developmental toxicity of DM and new insights into the mechanism of DM toxicity.

Chen C et al. (2003) Exp Gerontol "A high-throughput screening system for genes extending life-span."

Chen C, Desmyter L, Verstraelen J, Vanfleteren J, Braeckman B, Contreras R, Borgonie G, Dewaele S

[Exp Gerontol, 2003]

We developed a high-throughput functional genomic screening system that allows identification of genes prolonging life-span in the baker's yeast Saccharomyces cerevisiae. The method is based on isolating yeast mother cells with extended number of cell divisions as indicated by the increased number of bud scars on their surface. Fluorescently labelled Wheat Germ Agglutinin was used for specific staining of chitin, a major component of bud scars. Screening of a human HepG2 cDNA expression library in yeast resulted in the isolation of 12 yeast transformants with a potentially prolonged life-span. The transgene in one of the lines was identified as ferritin light chain (FTL) and studied in more detail. Yeast cells containing FTL showed an enhanced iron and H2O2 resistance, a reduced cell death rate and an increased number of cell divisions. Overexpression of FTL in the nematode Caenorhabditis elegans resulted in a life-span increase of 8% confirming our yeast observations in a multicellular organism. Our data demonstrate that this method permits a fast screening of libraries for hunting genes involved in

Chen C et al. (2011) Cell "An intercellular heme-trafficking protein delivers maternal heme to the embryo during development in C. elegans."

Dailey HA, Chen C, Sinclair J, Samuel TK, Hamza I

[Cell, 2011]

Extracellular free heme can intercalate into membranes and promote damage to cellular macromolecules. Thus it is likely that specific intercellular pathways exist for the directed transport, trafficking, and delivery of heme to cellular destinations, although none have been found to date. Here we show that Caenorhabditis elegans HRG-3 is required for the delivery of maternal heme to developing embryos. HRG-3 binds heme and is exclusively secreted by maternal intestinal cells into the interstitial fluid for transport of heme to extraintestinal cells, including oocytes. HRG-3 deficiency results either in death during embryogenesis or in developmental arrest immediately post-hatching-phenotypes that are fully suppressed by maternal but not zygotic hrg-3 expression. Our results establish a role for HRG-3 as an intercellular heme-trafficking protein.

Chen C et al. (2014) PLoS Genet "An ER complex of ODR-4 and ODR-8/Ufm1 specific protease 2 promotes GPCR maturation by a Ufm1-independent mechanism."

Hegde RS, Chen C, De Bono M, Weber KP, Itakura E

[PLoS Genet, 2014]

Despite the importance of G-protein coupled receptors (GPCRs) their biogenesis is poorly understood. Like vertebrates, C. elegans uses a large family of GPCRs as chemoreceptors. A subset of these receptors, such as ODR-10, requires the odr-4 and odr-8 genes to be appropriately localized to sensory cilia. The odr-4 gene encodes a conserved tail-anchored transmembrane protein; the molecular identity of odr-8 is unknown. Here, we show that odr-8 encodes the C. elegans ortholog of Ufm1-specific protease 2 (UfSP2). UfSPs are cysteine proteases identified biochemically by their ability to liberate the ubiquitin-like modifier Ufm1 from its pro-form and protein conjugates. ODR-8/UfSP2 and ODR-4 are expressed in the same set of twelve chemosensory neurons, and physically interact at the ER membrane. ODR-4 also binds ODR-10, suggesting that an ODR-4/ODR-8 complex promotes GPCR folding, maturation, or export from the ER. The physical interaction between human ODR4 and UfSP2 suggests that this complex's role in GPCR biogenesis may be evolutionarily conserved. Unexpectedly, mutant versions of ODR-8/UfSP2 lacking catalytic residues required for protease activity can rescue all odr-8 mutant phenotypes tested. Moreover, deleting C. elegans ufm-1 does not alter chemoreceptor traffic to cilia, either in wild type or in odr-8 mutants. Thus, UfSP2 proteins have protease- and Ufm1-independent functions in GPCR biogenesis.