Gene co-regulation and co-expression in the aryl hydrocarbon receptor-mediated transcriptional regulatory network in the mouse liver.
Arch Toxicol
; 94(1): 113-126, 2020 01.
Article
en En
| MEDLINE
| ID: mdl-31728591
Four decades after its discovery, the aryl hydrocarbon receptor (AHR), a ligand-inducible transcription factor (TF) activated by the persistent environmental contaminant 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), remains an enigmatic molecule with a controversial endogenous role. Here, we have assembled a global map of the AHR gene regulatory network in female C57BL/6 mice orally gavaged with 30 µg/kg of TCDD from a combination of previously published gene expression and genome-wide TF-binding data sets. Using Kohonen self-organizing maps and subspace clustering, we show that genes co-regulated by common upstream TFs in the AHR network exhibit a pattern of co-expression. Directly bound, indirectly bound, and non-genomic AHR target genes exhibit distinct expression patterns, with the directly bound targets associated with highest median expression. Interestingly, among the directly bound AHR target genes, the expression level increases with the number of AHR-binding sites in the proximal promoter regions. Finally, we show that co-regulated genes in the AHR network activate distinct groups of downstream biological processes. Although the specific findings described here are restricted to hepatic effects under short-term TCDD exposure, this work describes a generalizable approach to the reconstruction and analysis of transcriptional regulatory cascades underlying cellular stress response, revealing network hierarchy and the nature of information flow from the initial signaling events to phenotypic outcomes. Such reconstructed networks can form the basis of a new generation of quantitative adverse outcome pathways.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores de Hidrocarburo de Aril
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico
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Redes Reguladoras de Genes
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Dibenzodioxinas Policloradas
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Hígado
Límite:
Animals
Idioma:
En
Revista:
Arch Toxicol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Alemania