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Identification of a functional antioxidant response element at the HIF1A locus.

ABSTRACT: Reactive oxygen species (ROS), which are a byproduct of oxidative metabolism, serve as signaling molecules in a number of physiological settings. However, if their levels are not tightly maintained, excess ROS lead to potentially cytotoxic oxidative stress. Accordingly, several transcriptional regulatory networks have evolved to include components that are highly ROS-responsive. Depending on the context, these regulatory networks can leverage ROS to respond to nutrient conditions, metabolism, or other physiological signals, or to respond to oxidative stress. However, ROS signaling is complex, so regulatory interactions between various ROS-responsive transcription factors are still being mapped out. Here we show that the transcription factor NRF2, a key regulator of the adaptive response to oxidative stress, directly regulates expression of HIF1A, which encodes HIF1?, a key transcriptional regulator of the adaptive response to hypoxia. We used an integrative genomics approach to identify HIF1A as a ROS-responsive transcript and we found an NRF2-bound antioxidant response element (ARE) approximately 30 kilobases upstream of HIF1A. This ARE sequence is deeply conserved, and we verified that it is directly bound and activated by NRF2. In addition, we found that HIF1A is upregulated in breast and bladder tumors with high NRF2 activity. Taken together, our results demonstrate that NRF2 targets a functional ARE at the HIF1A locus, and reveal a direct regulatory connection between two important oxygen responsive transcription factors.

SUBMITTER: Lacher SE

PROVIDER: S-EPMC6146589 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Identification of a functional antioxidant response element at the HIF1A locus.

Lacher Sarah E SE Levings Daniel C DC Freeman Samuel S Slattery Matthew M

Redox biology 20180830

Reactive oxygen species (ROS), which are a byproduct of oxidative metabolism, serve as signaling molecules in a number of physiological settings. However, if their levels are not tightly maintained, excess ROS lead to potentially cytotoxic oxidative stress. Accordingly, several transcriptional regulatory networks have evolved to include components that are highly ROS-responsive. Depending on the context, these regulatory networks can leverage ROS to respond to nutrient conditions, metabolism, or ...[more]

PMID: 30241031

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Project description:The transcription factor NFE2L2 (Nuclear Factor, Erythroid 2-Like 2, or NRF2) plays a key role in maintaining the redox state within cells. Characterization of this pathway has extended to fish, most notably zebrafish (Danio rerio), in which two paralogs of the transcription factor exist: Nrf2a, an activator, and Nrf2b, a negative regulator during embryogenesis. Only one ARE target has been thoroughly delineated in zebrafish, and this deviated from the canonical sequence derived from studies in mammals. In general, the mechanistic pathway has not been characterized in non-model aquatic organisms that are commonly exposed to environmental pollutants. The current study compares the zebrafish paralogs to those found in a non-model teleost, the ecologically important salmonid, Oncorhnychus kisutch (coho salmon). Two salmon paralogs, Nrf2A and -2B, described here were found to possess only slightly greater identity between one another (84% of amino acids) than to the singleton ortholog of the esocid Esox lucius (80-82%), the nearest non-salmonid outgroup. Unlike one of the zebrafish forms, each is a strong activating factor based on sequence homology and in vitro testing. To uncover functional target AREs in coho, promoter flanking sequences were isolated for five genes that protect cells against oxidative stress: heme oxygenase 1, peroxiredoxin 1, glutamate-cysteine ligase, and the glutathione S-transferases pi and rho (hmox1, prdx1, gclc, gstp, and gstr). All except gstr had functional elements and all fit the standard mammalian-derived canonical sequence, unlike the motif found in zebrafish gstp. Expression studies demonstrate the presence of both Nrf2 paralogs in multiple organs, although in differing ratios. Collectively, our findings extend the conservation of Nrf2 and the ARE to salmonids, and should help inform future work in teleosts on mechanisms of redox control, as well as responsiveness of this pathway and its downstream antioxidant gene targets to chemical exposures in the environment.

Project description:Oxidative stress after burn injury induces inflammatory and hypermetabolic responses associated with adverse outcomes. We propose that antioxidant and trace element supplementation may reduce oxidative stress and subsequently alleviate inflammation and hypermetabolism, thus improving clinical outcomes. We conducted a cohort study of adult patients with an acute burn injury admitted to our provincial burn center. Patients in the antioxidant group received an intravenous infusion of multivitamins and trace elements for the first 14 days after admission. The inflammatory profile was assessed at early time points, < 14 days postburn, and later time points, ≥ 15 days postburn, and included interleukin (IL)-1β, interferon-γ, IL-1 receptor antagonist, IL-6, granulocyte-macrophage colony-stimulating factor, and FMS-like tyrosine kinase 3 ligand. Hypermetabolism was assessed by resting energy expenditure. Clinical outcomes included mortality, morbidities, hospital length of stay, and infections including days to the last positive culture after injury. We studied 172 patients, mean age 49 ± 17 years and 33 ± 13% TBSA burned, with 91 controls and 81 patients in the antioxidant group. Patients in the antioxidant group had significantly lower levels of inflammatory markers at both early and late time points, P < .05. Antioxidant treatment was associated with decreased measure of hypermetabolism, P < .05. Morbidity and mortality were not significantly different between groups. Length of hospital stay was significantly shorter in the antioxidant group when adjusted for patient demographics and injury characteristics (risk ratio (RR), 0.78; 95% confidence interval (CI), 0.66-0.92). In the antioxidant group, while infections were not different, the last positive culture post-injury was documented at median 19 days (Interquartile range (IQR), 11-43 days) compared with controls at 35 days (IQR, 15-59 days), P = .012. Patients receiving antioxidant and trace element supplementation had reduced markers of burn stress-induced inflammation; they were also associated with a decreased hypermetabolic response, shorter length of stay, and improved bacterial clearance.

Dataset Information

Identification of a functional antioxidant response element at the HIF1A locus.

Publications

Identification of a functional antioxidant response element at the HIF1A locus.

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