Biology subjects

Holdorf, A. D.

Publications and source records attributed to Holdorf, A. D..

3 recordsLinked to original sources

bioRxiv2020

WormPaths: Caenorhabditis elegans metabolic pathway annotation and visualization

In our group, we aim to understand metabolism in the nematode Caenorhabditis elegans and its relationships with gene expression, physiology and the response to therapeutic drugs. On March 15, 2020, a stay-at-home order was put into effect in the state of Massachusetts, USA, to flatten the curve of the spread of the novel SARS-CoV2 virus that causes COVID-19. For biomedical researchers in our state, this meant putting a hold on experiments for nine weeks until May 18, 2020. To keep the lab engaged and productive, and to enhance communication and collaboration, we embarked on an in-lab project that we all found important but that we never had the time for: the detailed annotation and drawing of C. elegans metabolic pathways. As a result, we present WormPaths, which is composed of two parts: 1) the careful manual annotation of metabolic genes into pathways, categories and levels, and 2) 66 pathway maps that include metabolites, metabolite structures, genes, reactions, and pathway connections between maps. These maps are available on our WormFlux website. We show that WormPaths provides easy-to-navigate maps and that the different levels in WormPaths can be used for metabolic pathway enrichment analysis of transcriptomic data. In the unfortunate event of additional lockdowns, we envision further developing these maps to be more interactive, with an analogy of road maps that are available on mobile devices.

genetics↗

bioRxiv2019

WormCat: an online tool for annotation and visualization of Caenorhabditis elegans genome-scale data

The emergence of large gene expression datasets has revealed the need for improved tools to identify enriched gene categories and visualize enrichment patterns. While Gene Ontogeny (GO) provides a valuable tool for gene set enrichment analysis, it has several limitations. First, it is difficult to graphically compare multiple GO analyses. Second, genes from some model systems are not well represented. For example, around 30% of Caenorhabditis elegans genes are missing from analysis in commonly used databases. To allow categorization and visualization of enriched C. elegans gene sets in different types of genome-scale data, we developed WormCat, a web-based tool that uses a near-complete annotation of the C. elegans genome to identify co-expressed gene sets and scaled heat map for enrichment visualization. We tested the performance of WormCat using a variety of published transcriptomic datasets and show that it reproduces major categories identified by GO. Importantly, we also found previously unidentified categories that are informative for interpreting phenotypes or predicting biological function. For example, we analyzed published RNA-seq data from C. elegans treated with combinations of lifespan-extending drugs where one combination paradoxically shortened lifespan. Using WormCat, we identified sterol metabolism as a category that was not enriched in the single or double combinations but emerged in a triple combination along with the lifespan shortening. Thus, WormCat identified a gene set with potential phenotypic relevance that was not uncovered with previous GO analysis. In conclusion, WormCat provides a powerful tool for the analysis and visualization of gene set enrichment in different types of C. elegans datasets.

bioinformatics↗

bioRxiv2018

A Persistence Detector for Metabolic Network Rewiring in an Animal

Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental signals. Gene regulatory network circuitries known as coherent type 1 feed-forward loops (FFLs) with AND-logic gates have been proposed to function as a persistence detector because it generates a delay in target activation and prevents target induction unless the input signal is sustained. While such a circuit has been found for the L-arabinose utilization system in E. coli, their existence and relevance multicellular organisms has remained unclear. Here, we identify the first persistence detector in an animal that redirects propionate breakdown to a shunt pathway when flux through the canonical propionate breakdown pathway is perturbed. We propose that this mechanism has evolved to ensure the shunt pathway stays off unless propionate accumulation is persistent because the shunt pathway generates highly toxic acrylate. Our study uniquely connects persistence detector circuitry to a physiological response in an animal.

systems biology↗