Nrf2 regulates haematopoietic stem cell function

Tsai, Jennifer J.; Dudakov, Jarrod A; Takahashi, Koichi; Shieh, Jae‐Hung; Velardi, Enrico; Holland, Aliya; Singer, Natalie V.; West, Mallory L.; Smith, Odette M.; Young, Lauren; Shono, Yusuke; Ghosh, Arnab; Hanash, Alan M.; Tran, Hien T.; Moore, Malcolm A.S.; Brink, Marcel R.M. van den

doi:10.1038/ncb2699

Cited by 176 publications

(183 citation statements)

References 32 publications

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“…All these miRNAs have been shown to be of interest in AML with miR-146a being shown to have low expression in AML, which correlates with high expression of its target gene CXCR4, 38 which in a separate study has been shown to be regulated by NRF2 in human HSC. 39 Consequently in human AML, NRF2 not only regulates key genes involved in the reaction to oxidative stress but also regulates miRNAs that appear to have a broader impact on gene expression and regulation.…”

Section: Discussionmentioning

confidence: 99%

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

et al. 2014

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Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics.

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Section: Discussionmentioning

confidence: 99%

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

et al. 2014

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“…Nrf2 deficiency has been associated with hyperproliferation of hematopoietic stem cells (28), proinflammatory T-cell differentiation (15), and exacerbation of EAE (14). Because Nrf2 −/− mice can develop more severe EAE, investigators who previously evaluated the role of Nrf2 in DMF-mediated treatment of chronic EAE, used an attenuated protocol in Nrf2 −/− mice (3).…”

Section: Discussionmentioning

confidence: 99%

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Schulze-Topphoff

Varrin‐Doyer

Pekarek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

245

202

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Dimethyl fumarate (DMF) (BG-12, Tecfidera) is a fumaric acid ester (FAE) that was advanced as a multiple sclerosis (MS) therapy largely for potential neuroprotection as it was recognized that FAEs are capable of activating the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, DMF treatment in randomized controlled MS trials was associated with marked reductions in relapse rate and development of active brain MRI lesions, measures considered to reflect CNS inflammation. Here, we investigated the antiinflammatory contribution of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE). C57BL/6 wild-type (WT) and Nrf2-deficient (Nrf2 −/− ) mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (p35-55) for EAE induction and treated with oral DMF or vehicle daily. DMF protected WT and Nrf2 −/− mice equally well from development of clinical and histologic EAE. The beneficial effect of DMF treatment in Nrf2 −/− and WT mice was accompanied by reduced frequencies of IFN-γ and IL-17-producing CD4 + cells and induction of antiinflammatory M2 (type II) monocytes. DMF also modulated B-cell MHC II expression and reduced the incidence of clinical disease in a B-cell-dependent model of spontaneous CNS autoimmunity. Our observations that oral DMF treatment promoted immune modulation and provided equal clinical benefit in acute EAE in Nrf2 −/− and WT mice, suggest that the antiinflammatory activity of DMF in treatment of MS patients may occur through alternative pathways, independent of Nrf2.multiple sclerosis | dimethyl fumarate | Nrf2 | EAE | M2 monocytes

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“…Keap1 deletion in mouse causes hyperkeratosis in the esophagus and forestomach, and Nrf2 deletion causes defects in adipogenesis and in hematopoiesis Pi et al, 2010;Tsai et al, 2013). Lossof-function mutations in dKeap1 and in cncC cause larval lethality (Veraksa et al, 2000;Sykiotis and Bohmann, 2008).…”

Section: Introductionmentioning

confidence: 99%

Visualization of the Drosophila dKeap1-CncC interaction on chromatin illumines cooperative, xenobiotic-specific gene activation

Huai

Kerppola

2014

Development

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Interactions among transcription factors control their physiological functions by regulating their binding specificities and transcriptional activities. We implement a strategy to visualize directly the genomic loci that are bound by multi-protein complexes in single cells in Drosophila. This method is based on bimolecular fluorescence complementation (BiFC) analysis of protein interactions on polytene chromosomes. Drosophila Keap1 (dKeap1)-CncC complexes localized to the nucleus and bound chromatin loci that were not bound preferentially by dKeap1 or CncC when they were expressed separately. dKeap1 and CncC binding at these loci was enhanced by phenobarbital, but not by tert-butylhydroquinone (tBHQ) or paraquat. Endogenous dKeap1 and CncC activated transcription of the Jheh (Jheh1, Jheh2, Jheh3) and dKeap1 genes at these loci, whereas CncC alone activated other xenobiotic response genes. Ectopic dKeap1 expression increased CncC binding at the Jheh and dKeap1 gene loci and activated their transcription, whereas dKeap1 inhibited CncC binding at other xenobiotic response gene loci and suppressed their transcription. The combinatorial chromatin-binding specificities and transcriptional activities of dKeap1-CncC complexes mediated the selective activation of different sets of genes by different xenobiotic compounds, in part through feed-forward activation of dKeap1 transcription.

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Nrf2 regulates haematopoietic stem cell function

Cited by 176 publications

References 32 publications

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Visualization of the Drosophila dKeap1-CncC interaction on chromatin illumines cooperative, xenobiotic-specific gene activation

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