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Comparison of hepatic NRF2 and AHR binding in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treated mice demonstrates NRF2-independent PKM2 induction

ABSTRACT: Comparison of hepatic NRF2 and AHR binding in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treated mice demonstrates NRF2-independent PKM2 induction

PROVIDER: PRJNA432209 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6653150.fastq.gz	Fastqsanger.gz
	SRR6653160.fastq.gz	Fastqsanger.gz
	SRR6653170.fastq.gz	Fastqsanger.gz
	SRR6653180.fastq.gz	Fastqsanger.gz
	SRR6653190.fastq.gz	Fastqsanger.gz

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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)

Project description: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.

2018-06-07 | GSE109863 | GEO

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 (ChIP-Seq)

2018-06-07 | GSE109865 | GEO

Nrf2 protects against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced oxidative injury and steatohepatitis.

Project description:Previous studies demonstrate that Nrf2, a master regulator of antioxidative responses, is essential in mediating induction of many antioxidative enzymes by acute activation of the AhR. However, the role of Nrf2 in protecting against oxidative stress and DNA damage induced by sustained activation of the AhR remains unknown and was investigated herein. Tissue and blood samples were collected from wild-type (WT) and Nrf2-null mice 21 days after administration of a low-toxic dose (10 μg/kg ip) of TCDD. Only Nrf2-null mice lost body weight after TCDD treatment; however, blood levels of ALT were not markedly changed in either genotype, indicating a lack of extensive necrosis. Compared to livers of TCDD-treated WT mice, livers of TCDD-treated Nrf2-null mice had: 1) degenerated hepatocytes, lobular inflammation, marked fat accumulation, and higher mRNA expression of inflammatory and fibrotic genes; 2) depletion of glutathione, elevation in lipid peroxidation and marker of DNA damage; 3) attenuated induction of phase-II enzymes Nqo1, Gsta1/2, and Ugt2b35 mRNAs, but higher induction of cytoprotective Ho-1, Prdx1, Trxr1, Gclc, and Epxh1 mRNAs; 4) higher mRNA expression of Fgf21 and triglyceride-synthesis genes, but down-regulation of bile-acid-synthesis genes and cholesterol-efflux transporters; and 5) trend of induction/activation of c-jun and NF-kB. Additionally, TCDD-treated Nrf2-null mice had impaired adipogenesis in white adipose tissue. In conclusion, Nrf2 protects livers of mice against oxidative stress, DNA damage, and steatohepatitis induced by TCDD-mediated sustained activation of the AhR. The aggravated hepatosteatosis in TCDD-treated Nrf2-null mice is due to increased lipogenesis in liver and impaired lipogenesis in white adipose tissue.

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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)

Project description: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)

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2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Alters Lipid Metabolism and Depletes Immune Cell Populations in the Jejunum of C57BL/6 Mice

Project description:Dose-dependent jejunal epithelial gene expression was examined following repeated exposure (every 4 days for 28 days) to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These data were used to examine the effect of repeated TCDD exposure on jejunal differential gene expression, in order to investigate the role of the jejunum in TCDD-elicited steatohepatitis in C57BL/6.

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2,3,7,8-tetrachlorodibenzo-p-dioxin modifies alternative splicing in mouse liver

Project description:2,3,7,8-tetrachlorodibenzo-p-dioxin modifies alternative splicing in mouse liver

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RNA-sequencing of 14 diverse mouse strains treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Project description:The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor in the PAS superfamily of environmental sensors that is linked to several metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). Much remains unknown regarding the impact of genetic variation in AHR-driven disease, as past studies have focused on a small number of inbred strains. Recently, the presence of a wide-range of interindividual variability amongst humans was reported in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the prototypical ligand of the AHR. In this study, a panel of 14 diverse mouse strains were exposed to TCDD for 10 days to characterize the AHR-mediated response across genetic backgrounds. In this study, responses to TCDD are heavily-dependent on genetic background. While mice carry one of four Ahr alleles that impact the AHR-mediated responses, we observed significant intra-allelic variability suggesting the presence of novel genetic modifiers of AHR signaling. A regression-based approach was used to scan for genes regulated by the AHR and/or associated with TCDD-induced phenotypes. The approach identified seven genes, 2 of which are novel, that are likely regulated by the AHR based on association with hepatic TCDD burden (p≤0.05). Finally, we identified a gene, Dio1, which was associated with change in percent body fat across the diverse set of strains (p≤0.05). Overall, the results in this study exemplify the power of genetics-based approaches in identifying novel genes that are putatively regulated by the AHR.

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Project description:RNA-sequencing of 14 diverse mouse strains treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

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