Superfund Research Program
Title: Hepatic pyruvate kinase muscle isoform 2 (Pkm2) induction in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited oxidative stress is independent of NRF2 (RNA-Seq)
Accession Number: GSE109863
Link to Dataset: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE109863
Repository: Gene Expression Omnibus (GEO)
Data Type(s): Gene Expression
Experiment Type(s): Expression profiling by high throughput sequencing
Organism(s): Mus musculus
Summary: Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic oxidative stress following activation of the aryl hydrocarbon receptor (AhR). Our recent studies revealed induction of pyruvate kinase muscle isoform 2 (Pkm2) as a novel antioxidant response in normal differentiated hepatocytes. To investigate cooperative regulation between nuclear factor, erythroid derived 2, like 2 (Nrf2) and the AhR, hepatic ChIP-seq analyses were integrated with RNA-seq time course data from mice treated with TCDD for 2 - 168h. ChIP-seq analysis 2h following TCDD treatment revealed genome-wide changes in NRF2 binding. 842 NRF2 enriched regions were in the regulatory region of differentially expressed genes (DEGs) while 579 DEGs showed both NRF2 and AhR enrichment. Sequence analysis showed over-representation of AhR and NRF2 binding motifs in these regions, though presence of motifs were largely independent. NRF2 was negligibly enriched within the Pkm gene loci in a closed chromatin region despite its role in antioxidant defenses. Furthermore, TCDD induced Pkm2 in primary hepatocytes from wild-type and Nrf2 null mice, indicating NRF2 is not required. Although NRF2 and AhR cooperate in the regulation of gene expression associated with antioxidant responses, the induction of Pkm2 by TCDD is not dependent on ROS-mediated activation of NRF2.
Publication(s) associated with this dataset:- Nault R, Doskey CM, Fader KA, Rockwell CE, Zacharewski TR. 2018. Comparison of hepatic NRF2 and aryl hydrocarbon receptor binding in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated mice demonstrates NRF2-independent PKM2 induction. Mol Pharmacol 94(2):876-884. doi:10.1124/mol.118.112144 PMID:29752288 PMCID:6022803