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Single worm transcriptomics identifies a developmental core network of oscillating genes with deep conservation across nematodes.

ABSTRACT: High-resolution spatial and temporal maps of gene expression have facilitated a comprehensive understanding of animal development and evolution. In nematodes, the small body size represented a major challenge for such studies, but recent advancements have helped overcome this limitation. Here, we have implemented single worm transcriptomics (SWT) in the nematode model organism Pristionchus pacificus to provide a high-resolution map of the developmental transcriptome. We selected 38 time points from hatching of the J2 larvae to young adults to perform transcriptome analysis over 60 h of postembryonic development. A mean sequencing depth of 4.5 million read pairs allowed the detection of more than 23,135 (80%) of all genes. Nearly 3000 (10%) genes showed oscillatory expression with discrete expression levels, phases, and amplitudes. Gene age analysis revealed an overrepresentation of ancient gene classes among oscillating genes, and around one-third of them have 1:1 orthologs in C. elegans One important gene family overrepresented among oscillating genes is collagens. Several of these collagen genes are regulated by the developmental switch gene eud-1, indicating a potential function in the regulation of mouth-form plasticity, a key developmental process in this facultative predatory nematode. Together, our analysis provides (1) an updated protocol for SWT in nematodes that is applicable to many microscopic species, (2) a 1- to 2-h high-resolution catalog of P. pacificus gene expression throughout postembryonic development, and (3) a comparative analysis of oscillatory gene expression between the two model organisms P. pacificus and C. elegans and associated evolutionary dynamics.

SUBMITTER: Sun S

PROVIDER: S-EPMC8415380 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Single worm transcriptomics identifies a developmental core network of oscillating genes with deep conservation across nematodes.

Sun Shuai S Rödelsperger Christian C Sommer Ralf J RJ

Genome research 20210722 9

High-resolution spatial and temporal maps of gene expression have facilitated a comprehensive understanding of animal development and evolution. In nematodes, the small body size represented a major challenge for such studies, but recent advancements have helped overcome this limitation. Here, we have implemented single worm transcriptomics (SWT) in the nematode model organism <i>Pristionchus pacificus</i> to provide a high-resolution map of the developmental transcriptome. We selected 38 time p ...[more]

PMID: 34301622

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Project description:The discovery and development of novel anthelmintic classes is essential to sustain the control of socioeconomically important parasitic worms of humans and animals. With the aim of offering novel, lead-like scaffolds for drug discovery, Compounds Australia released the 'Open Scaffolds' collection containing 33,999 compounds, with extensive information available on the physicochemical properties of these chemicals. In the present study, we screened 14,464 prioritised compounds from the 'Open Scaffolds' collection against the exsheathed third-stage larvae (xL3s) of Haemonchus contortus using recently developed whole-organism screening assays. We identified a hit compound, called SN00797439, which was shown to reproducibly reduce xL3 motility by ≥ 70%; this compound induced a characteristic, "coiled" xL3 phenotype (IC50 = 3.46-5.93 μM), inhibited motility of fourth-stage larvae (L4s; IC50 = 0.31-12.5 μM) and caused considerable cuticular damage to L4s in vitro. When tested on other parasitic nematodes in vitro, SN00797439 was shown to inhibit (IC50 = 3-50 μM) adults of Ancylostoma ceylanicum (hookworm) and first-stage larvae of Trichuris muris (whipworm) and eventually kill (>90%) these stages. Furthermore, this compound completely inhibited the motility of female and male adults of Brugia malayi (50-100 μM) as well as microfilariae of both B. malayi and Dirofilaria immitis (heartworm). Overall, these results show that SN00797439 acts against genetically (evolutionarily) distant parasitic nematodes i.e. H. contortus and A. ceylanicum [strongyloids] vs. B. malayi and D. immitis [filarioids] vs. T. muris [enoplid], and, thus, might offer a novel, lead-like scaffold for the development of a relatively broad-spectrum anthelmintic. Our future work will focus on assessing the activity of SN00797439 against other pathogens that cause neglected tropical diseases, optimising analogs with improved biological activities and characterising their targets.

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Single worm transcriptomics identifies a developmental core network of oscillating genes with deep conservation across nematodes.

Publications

Single worm transcriptomics identifies a developmental core network of oscillating genes with deep conservation across nematodes.

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