Single-Nuclei RNA Sequencing Assessment of the Hepatic Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Nault, Rance; Fader, Kelly A.; Bhattacharya, Sudin; Zacharewski, Tim

doi:10.1016/j.jcmgh.2020.07.012

Cited by 54 publications

(72 citation statements)

References 52 publications

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“…Nault et al [10] collected a dataset of 16,015 single nuclei to assess the hepatic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD. In particular, they focused on the effect of TCDD on the 9, 951 hepatocytes cells along the central-portal axis.…”

Section: Resultsmentioning

confidence: 99%

Trajectory inference across multiple conditions with condiments: differential topology, progression, differentiation, and expression

Bézieux

Berge

Street

et al. 2021

Preprint

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In single-cell RNA-sequencing (scRNA-seq), gene expression is assessed individually for each cell, allowing the investigation of developmental processes, such as embryogenesis and cellular differentiation and regeneration, at unprecedented resolutions. In such dynamic biological systems, grouping cells into discrete groups is not reflective of the biology. Cellular states rather form a continuum, e.g., for the differentiation of stem cells into mature cell types. This process is often represented via a trajectory in a reduced-dimensional representation of the scRNA-seq dataset. While many methods have been suggested for trajectory inference, it is often unclear how to handle multiple biological groups or conditions, e.g., inferring and comparing the differentiation trajectories of wild-type and knock-out stem cell populations. In this manuscript, we present a method for the estimation and downstream interpretation of cell trajectories across multiple conditions. Our framework allows the interpretation of differences between conditions at the trajectory, cell population, and gene expression levels. We start by integrating datasets from multiple conditions into a single trajectory. By comparing the conditions along the trajectory's path, we can detect large-scale changes, indicative of differential progression. We also demonstrate how to detect subtler changes by finding genes that exhibit different behaviors between these conditions along a differentiation path.

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Section: Resultsmentioning

confidence: 99%

Trajectory inference across multiple conditions with condiments: differential topology, progression, differentiation, and expression

Bézieux

Berge

Street

et al. 2021

Preprint

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“…Adgre1 and Cd5l did not exhibit AhR genomic enrichment at 2 hrs suggesting increases were due to macrophages recruitment and/or proliferation while Csf1r induction may involve the AhR. The low number of macrophages within control livers confound distinguishing Adgre1 , Cd5l , and Csfr1 increases due to induction by TCDD from increased macrophage levels following infiltration into the liver and/or macrophages proliferation (Nault et al, 2020). TCDD also dose-dependently induced Acod1 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation

Orlowska

Fling

Nault

et al. 2021

Preprint

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2,3,7,8 –Tetrachlorodibenzo –p –dioxin (TCDD) is a persistent environmental contaminant and the prototypical ligand for the aryl hydrocarbon receptor (AhR). AhR mediates the effects of TCDD and related compounds, including the reprograming of intermediate metabolism. Untargeted metabolomics analysis of hepatic extracts prepared from mice orally gavaged with TCDD every 4 days for 28 days identified the dose –dependent induction of acrylyl –CoA, a highly reactive toxic intermediate produced during the metabolism of propionyl –CoA in the cobalamin (Cbl) –independent β –oxidation –like pathway. Acrylyl –CoA is a biomarker of inborn errors of metabolism associated with propionic and methylmalonic acidemia associated with Cbl deficiency, transport and/or defects in Cbl –dependent methylmalonyl –CoA mutase (MUT). Although TCDD repressed gene expression for both the canonical Cbl –dependent carboxylase and the alternate Cbl –independent β –oxidation –like pathways, inhibition occurred only at 30 μg/kg TCDD while acrylyl –CoA levels increased at ~3 μg/kg. In contrast, TCDD decreased serum Cbl and hepatic cobalt levels at ~3 μg/kg TCDD consistent with the dose –dependent increase in acrylyl –CoA levels. TCDD elicited negligible effects on the expression of genes associated with Cbl absorption, transport, trafficking and derivatization to 5 –deoxy –adenosylcobalamin (AdoCbl), the required MUT cofactor. In addition, TCDD induced the decarboxylation of cis –aconitate to itaconate by Acod1. Itaconate can then be activated to itaconyl –CoA, a MUT suicide inactivator that forms an adduct with AdoCbl, blocking MUT activity and reducing Cbl levels. Collectively, these results suggest MUT activity was impaired due to Cbl depletion by TCDD causing propionyl –CoA metabolism to be redirected to the alternate Cbl –independent β –oxidation –like pathway resulting in hepatic acrylyl –CoA accumulation.

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“…Nault et al, 2021 70 . snRNA-seq data from the livers of mice gavaged with 2,3,7,8-tetrachlorodibenzo-p-dioxin or sesame oil vehicle was obtained from GEO (accession: GSE148339).…”

Section: Methodsmentioning

confidence: 99%

Confronting false discoveries in single-cell differential expression

Squair

Gautier

Kathe

et al. 2021

Preprint

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Differential expression analysis in single-cell transcriptomics enables the dissection of cell-type-specific responses to perturbations such as disease, trauma, or experimental manipulation. While many statistical methods are available to identify differentially expressed genes, the principles that distinguish these methods and their performance remain unclear. Here, we show that the relative performance of these methods is contingent on their ability to account for variation between biological replicates. Methods that ignore this inevitable variation are biased and prone to false discoveries. Indeed, the most widely used methods can discover hundreds of differentially expressed genes in the absence of biological differences. Our results suggest an urgent need for a paradigm shift in the methods used to perform differential expression analysis in single-cell data.

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Single-Nuclei RNA Sequencing Assessment of the Hepatic Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Cited by 54 publications

References 52 publications

Trajectory inference across multiple conditions with condiments: differential topology, progression, differentiation, and expression

Trajectory inference across multiple conditions with condiments: differential topology, progression, differentiation, and expression

Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation

Confronting false discoveries in single-cell differential expression

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