What does your cell really do? Model-based assessment of mammalian cells metabolic functionalities using omics data

Abstract

Large-scale omics experiments have become standard in biological studies, leading to a deluge of data. However, researchers still face the challenge of connecting changes in the omics data to changes in cell functions, due to the complex interdependencies between genes, proteins and metabolites. Here we present a novel framework that begins to overcome this problem by allowing users to infer how metabolic functions change, based on omics data. To enable this, we curated and standardized lists of metabolic tasks that mammalian cells can accomplish. We then used genome-scale metabolic networks to define gene modules responsible for each specific metabolic task. We further developed a framework to overlay omics data on these modules to predict pathway usage for each metabolic task. The proposed approach allows one to directly predict how changes in omics experiments change cell or tissue function. We further demonstrated how this new approach can be used to leverage the metabolic functions of biological entities from the single cell to their organization in tissues and organs using multiple transcriptomic datasets (human and mouse). Finally, we created a web-based CellFie module that has been integrated into the list of tools available in GenePattern (www.genepattern.org) to enable adoption of the approach.

Deciphering cell–cell interactions and communication from gene expression

“…For example, metabolite secretion data have been included in communication studies by considering the expression of the producing enzymes 85 . In this regard, the production of specific metabolites can be inferred from transcriptomic data 86 , 87 ; however, metabolite concentrations cannot be directly predicted, so concentration-dependent interactions cannot be assessed. Among other efforts, information about downstream signalling gene products and gene regulatory networks can be included 25 , 54 by weighing the potential of using a communication pathway given the intracellular effect on a receiver cell.…”

Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity

“…These activities have also been formulated in a computational modeling platform to simulate PUL activity (Eilam et al, 2014). As a further generalization of PUL estimation beyond comprehensive genome annotation or mechanistic modeling, we used a pathway-based approach by modeling catabolism of each major glycan as a metabolic task in order to predict bacteria involved in catabolism of HS (Richelle et al, 2018(Richelle et al, , 2019(Richelle et al, , 2020.…”

“…We curated a metabolic task (i.e. a group of catabolic reactions necessary to transition between metabolites (Richelle et al, 2020)) that describes HS modification (Fig. 1B).…”

“…The HS modification gene set is a metabolic task, i.e. a group of reactions necessary to transition between metabolites (Richelle et al, 2020) used to describe a complete pathway of HS modification. Pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG, ec00531, (Kanehisa et al, 2017)), in combination with literature annotation of these pathways for specific bacteria (Hobbs et al, 2018;Robb et al, 2017;Ndeh et al, 2017), were used to identify reactions (enzyme commission (EC) numbers) associated with the modification task.…”

“…A pseudocount was added to each count and log-transformed, ( To quantify the HS-catabolic capacity ( -) of each organism, i, with genes, g, we analyzed the expression of all glycosylation-related genes within the catabolic task. Adapted from metabolic task analysis (Richelle et al, 2018(Richelle et al, , 2019(Richelle et al, , 2020, the catabolic capacity of a microbe is a contextsensitive measure that accommodates rate-limiting or low-abundance enzymes and can therefore accommodate microbial gene transience. Activation of the glycan degrading metabolic task (Richelle et al, 2020), was calculated as the minimum EC activation; the maximum activation of genes performing the EC reaction within an organism.…”