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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.

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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 (ChIP-Seq)

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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 ?g/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)

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

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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

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-06-07 | GSE109866 | GEO