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1
García-Rodríguez, Fernando M., and Nicolás Toro. "Sinorhizobium meliloti nfe (Nodulation Formation Efficiency) Genes Exhibit Temporal and Spatial Expression Patterns Similar to Those of Genes Involved in Symbiotic Nitrogen Fixation." Molecular Plant-Microbe Interactions® 13, no. 6 (June 2000): 583–91. http://dx.doi.org/10.1094/mpmi.2000.13.6.583.
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The nfe genes (nfeA, nfeB, and nfeD) are involved in the nodulation efficiency and competitiveness of the Sinorhizobium meliloti strain GR4 on alfalfa roots. The nfeA and nfeB genes are preceded by functional nif consensus sequences and NifA binding motifs. Here, we determined the temporal and spatial expression patterns of the nfe genes in symbiosis with alfalfa. Translational fusions of the nfe promoters with the gusA gene and reverse transcription-polymerase chain reaction analyses indicate that they are expressed and translated within mature nitrogen-fixing nodules and not during early steps of nodule development. Within the nodules the three nfe genes exhibit a spatial expression pattern similar to that of genes involved in symbiotic nitrogen fixation. We show that nfeB and nfeD genes are expressed not only from their own promoters but also from the upstream nfe promoter sequences. Furthermore, with the use of specific antibodies the NfeB and NfeD proteins were detected within the root nodule bac-teroid fraction. Finally, NfeB was inmunolocalized in the bacteroid cell membrane whereas NfeD was detected in the bacteroid cytoplasm.
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Sanders, Mathijs A., Annelieke Zeilemakers, Jasper Koenders, Remco Hoogenboezem, François Kavelaars, Rob Henderson, Bob Lowenberg, and Peter J. M. Valk. "The Gene Encoding Nuclear Erythroid Factor 2 (NFE2) Is Recurrently Mutated in Acute Myeloid Leukemia." Blood 120, no. 21 (November 16, 2012): 1392. http://dx.doi.org/10.1182/blood.v120.21.1392.1392.
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Abstract Abstract 1392 Background: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the accumulation of various acquired (cyto)genetic aberrations in the leukemic blasts. Novel state-of-the-art sequencing technologies enable sequencing of complete disease genomes. Methods: We have used Complete Genomics (CG) next-generation sequencing to identify novel recurrent mutations in AML. We have selected a single AML case, WHO: AML with maturation, FAB: M2, karyotype 45X, -Y and a NPM1 mutation. Mutations in FLT3, CEBPA, ASXL1, IDH1, IDH2, NRAS, KRAS and DNMT3A were absent. By whole genome sequencing of the AML and its corresponding remission sample, we identified acquired mutations in the protein coding regions of 31 genes (CG somatic score >0.1), including NPM1 and PTPN11. Results: Interestingly, a frame-shift mutation in the protein coding region of the Nuclear Erythroid Factor 2 (NFE2) transcription factor gene was identified and acquisition of this mutation was confirmed by Sanger sequencing of both AML and remission samples. The complete NFE2 gene of the index AML patient was sequenced but no additional mutation was present, nor was the remaining allele affected by deletions and/or amplifications. The index mutation introduces a premature stop codon (PTC) in the NFE2 gene, upstream of the region encoding the bZIP domain. To investigate if NFE2 would be recurrently mutated in AML, we screened a cohort of 1139 AML cases by denaturing high performance liquid chromatography (dHPLC) analyses for mutations in a 350bp region surrounding the index mutation in the NFE2 gene. We identified NFE2 mutations in 5 additional cases of AML. Subsequently, we screened the complete NFE2 gene in 254 randomly selected AML cases by Roche 454 sequencing. This analysis revealed 8 NFE2 mutant cases in total. These results indicate that approximately 3.5% (8/254) of unselected primary AML cases carry NFE2 mutations. The acquisition of the NFE2 mutations was confirmed by Sanger sequencing of all NFE2mutant AML cases and their corresponding derived T cells. Frame shift mutations upstream of the NFE2 bZIP domain introducing PTCs were present in 6 out of all identified NFE2 mutant cases (n=13). The remaining cases carried non-synonymous NFE2 mutations and a single case an in-frame insertion/deletion. In our cohort of molecularly and clinically well-characterized cohort of AML patients the NFE2 mutations were not associated with any clinical characteristic or any other (cyto)genetic aberration. Discussion: It is currently unclear if the NFE2 mutations would lead to a gain-of-function or a loss-of-function. Nfe2-deficient mice lack circulating platelets and die of hemorrhage; their megakaryocytes showed no cytoplasmic platelet formation. In addition, NFE2 transgenic mice show MPNs, including thrombocytosis, and spontaneous transformation to acute myeloid leukemia. However, the NFE2 mutations did not associate with abnormal platelet counts in the affected AML cases, nor did the AML cases have consistent megakaryocyte abnormalities. Mutant NFE2 is currently functionally studied by introduction into various cell line models and mouse primary bone marrow. Conclusion: In conclusion, we have identified recurrent mutation in the transcription factor gene NFE2 in a subset of AML cases. The exact role of mutant NFE2 is currently being investigated. Disclosures: No relevant conflicts of interest to declare.
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Peeken, Jan C., Jonas S. Jutzi, Julius Wehrle, Christoph Koellerer, Hans F. Staehle, Heiko Becker, Elias Schoenwandt, et al. "Epigenetic regulation of NFE2 overexpression in myeloproliferative neoplasms." Blood 131, no. 18 (May 3, 2018): 2065–73. http://dx.doi.org/10.1182/blood-2017-10-810622.
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Key Points Overexpression of NFE2 in MPNs is associated with H3Y41 phosphorylation by JAK2V617F. JMJD1C is an NFE2 target gene and acts in a positive feedback loop contributing to NFE2 overexpression in MPNs.
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Steiner, Laurie A., Vincent P. Schulz, Yelena Maksimova, Milind Mahajan, David M. Bodine, and Patrick G. Gallagher. "Dynamic CO-Localization of GATA1, NFE2, and EKLF and Changes in Gene Expression During Hematopoiesis." Blood 116, no. 21 (November 19, 2010): 741. http://dx.doi.org/10.1182/blood.v116.21.741.741.
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Abstract Abstract 741 Regulation of lineage choice during the development and differentiation of erythroid cells in hematopoiesis is a complex process. GATA1, NFE2, and EKLF are transcription factors critical for erythropoiesis. Focused studies, including detailed analyses of the human beta globin gene locus and a select group of erythrocyte membrane protein genes, have revealed that these three transcription factors may co-localize at common regulatory sites in erythroid-expressed genes. To address the hypothesis that GATA1, NFE2, and EKLF frequently co-localize on critical regulatory elements responsible for cell-type specific gene expression during erythropoiesis, chromatin immunoprecipitation coupled with ultrahigh throughput sequencing (ChIP-seq) was used to identify sites of GATA1, NFE2, and EKLF occupancy in human primary hematopoietic stem and progenitor cells (HSPCs) and human primary erythroid cells. ChIP was done using CD34+ HSPCs prepared by immunomagnetic bead selection and cultured CD71+/GPA+ erythroid cells (R3/R4 population) using antibodies against GATA1, NF-E2, and EKLF. The MACS algorithm (Zhang et al. Genome Biol, 2008) was used to identify regions of DNA-protein interaction, with a p-value ≤10e-5. Sites identified by MACS were ordered by p-value, and the 7000 sites with the most stringent p-values were selected for further analysis. Sites which occurred within 200bp of each other were treated as a single site. Unexpectedly, sites of GATA1, NFE2, and EKLF occupancy were common in HSPCs, with 6643 GATA1, 6657 NFE2, and 6579 EKLF sites identified, respectively. Sites identified in HSPCs were primarily in enhancers (>1kb from a RefSeq gene; 44% of GATA1, 49% of NFE2, and 51% of EKLF sites) and in introns (32% of GATA1, 34% of NFE2, and 34% of EKLF sites), with only a few sites at proximal promoters (within 1kb of a TSS; 7% of GATA1, 6% of NFE2, and 7% EKLF sites.) In erythroid cells, 6895 GATA1, 6907 NF-E2, and 6874 EKLF sites were identified. For all 3 factors, binding site occupancy varied greatly from that observed in HSPCs. Proximal promoter binding was much more common in erythroid cells than in HSPCs, with 19% of GATA1, 28% of NFE2 and 38% of EKLF sites found at promoters. Binding was frequently found at enhancers (41% of GATA, 38% NFE2, and 32% EKLF sites) and in introns (29% of GATA1, 26% of NFE2, and 21% of EKLF). To gain insight into three factor co-occupancy on a genome-wide scale, GATA1, EKLF, and NFE2 binding sites were compared using the Active Region Comparer (http://dart.gersteinlab. org/). Surprisingly, co-localization of all three factors was common in HSPCs, occurring at 2666 sites (40%, 40% and 45% of GATA1, NFE2, and EKLF sites). Sites of GATA1-NFE2-EKLF co-localization in HSPCs were located primarily at enhancers (51% of sites), in introns (32% of sites), and rarely at proximal promoters (6% of sites). In erythroid cells, co-localization of all three transcription factors was also common, occurring at 2445 sites (35%, 35%, and 36% of GATA1, NFE2, and EKLF sites, respectively). In contrast to HSPCs, sites of GATA1-NFE2-EKLF co-localization in erythroid cells were located primarily at proximal promoters (35% of sites) and enhancers (34% of sites), with co-localization in introns accounting for 20% of sites. A limited subset of sites, 1429 GATA1, 921 NFE2, and 1038 EKLF sites, were present in both HSPC and erythroid cells. Throughout the genome, there were only 233 sites of three factor co-localization in common in both HSPC and erythroid cells. Gene expression in HSPC and erythroid cell was analyzed via RNA hybridization to Illumina HumanHT-12 v3 Expression BeadChip arrays. In erythroid cells, genes with GATA1-NFE2-EKLF co-localization from 5kb upstream to 2kb downstream had significantly higher levels of mRNA expression than genes without GATA1-NFE2-EKLF co-localization (p<2.2e-16). The reverse was observed in HSPCs, where genes with GATA1-NFE2-EKLF co-localization had significantly lower levels of mRNA expression than genes without GATA1-NFE2-EKLF co-localization (p<7.3e-05). These data support the hypothesis that co-localization of GATA1, NFE2, and EKLF is a common finding in hematopoietic cells. Significant differences in factor co-localization and gene expression in HSPC and erythroid cells suggest that this coordinated binding orchestrates different patterns of gene expression during hematopoiesis. Disclosures: No relevant conflicts of interest to declare.
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Rost, Megan S., Ilya Shestopalov, Yang Liu, Andy H. Vo, Catherine E. Richter, Sylvia M. Emly, Francesca G. Barrett, et al. "Nfe2 is dispensable for early but required for adult thrombocyte formation and function in zebrafish." Blood Advances 2, no. 23 (November 30, 2018): 3418–27. http://dx.doi.org/10.1182/bloodadvances.2018021865.
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AbstractThe NFE2 transcription factor is expressed in multiple hematopoietic lineages with a well-defined role in regulating megakaryocyte biogenesis and platelet production in mammals. Mice deficient in NFE2 develop severe thrombocytopenia with lethality resulting from neonatal hemorrhage. Recent data in mammals reveal potential differences in embryonic and adult thrombopoiesis. Multiple studies in zebrafish have revealed mechanistic insights into hematopoiesis, although thrombopoiesis has been less studied. Rather than platelets, zebrafish possess thrombocytes, which are nucleated cells with similar functional properties. Using transcription activator-like effector nucleases to generate mutations in nfe2, we show that unlike mammals, zebrafish survive to adulthood in the absence of Nfe2. Despite developing severe thrombocytopenia, homozygous mutants do not display overt hemorrhage or reduced survival. Surprisingly, quantification of circulating thrombocytes in mutant 6-day-old larvae revealed no significant differences from wild-type siblings. Both wild-type and nfe2 null larvae formed thrombocyte-rich clots in response to endothelial injury. In addition, ex vivo thrombocytic colony formation was intact in nfe2 mutants, and adult kidney marrow displayed expansion of hematopoietic progenitors. These data suggest that loss of Nfe2 results in a late block in adult thrombopoiesis, with secondary expansion of precursors: features consistent with mammals. Overall, our data suggest parallels with erythropoiesis, including distinct primitive and definitive pathways of development and potential for a previously unknown Nfe2-independent pathway of embryonic thrombopoiesis. Long-term homozygous mutant survival will facilitate in-depth study of Nfe2 deficiency in vivo, and further investigation could lead to alternative methodologies for the enhancement of platelet production.
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Rost, Megan S., Ilya Shestopalov, Yang Liu, Andy H. Vo, Francesca Barrett, David L. Stachura, Leonard I. Zon, and Jordan A. Shavit. "Nfe2 Is Dispensable for Early, but Required for Adult Thrombocyte Formation and Function in Zebrafish." Blood 128, no. 22 (December 2, 2016): 2534. http://dx.doi.org/10.1182/blood.v128.22.2534.2534.
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Abstract The NFE2 transcription factor is expressed in multiple hematopoietic lineages with a well-defined role in regulating megakaryocyte biogenesis and platelet production in mammals. Mice deficient in NFE2 completely lack circulating platelets, causing early lethality due to neonatal hemorrhage. Recent data in mice suggest some differences in embryonic and adult thrombopoiesis, and overexpression of NFE2 in murine bone marrow cells increases megakaryocyte maturation and platelet release, suggesting a role for NFE2 in both early and late megakaryocyte development. Zebrafish have emerged as an excellent model for studying hematopoiesis and thrombopoiesis due to their external development, optical transparency, high fecundity, and conservation of nearly the entire hemostatic system. Rather than platelets, zebrafish possess thrombocytes - nucleated cells believed to be the functional equivalent in mammals. We designed TALENs to target exon 4 of zebrafish nfe2, producing two mutant strains containing either an 8 or 10 base pair deletion, both resulting in a frameshift and null allele. We tracked survival for over one year and found that unlike mammals, zebrafish survive into adulthood in the absence of Nfe2 function with no signs of overt bleeding or lethality. We bred the nfe2 mutation into a transgenic background in which thrombocytes and hematopoietic progenitor cells express green fluorescent protein (Tg(cd41:GFP)) and are characterized by GFPhigh and GFPlow expression, respectively. We performed flow cytometry analysis and found that the percentage of GFPhigh cells (circulating thrombocytes) in the peripheral blood was significantly decreased from 0.67% to 0.2% in homozygous mutants (p < 0.001). In contrast, the percentage of GFPlow cells in the kidney marrow, the site of hematopoiesis in adult zebrafish, was increased from 0.47% to 1.17% in nfe2-/- mutants (p < 0.001). Surprisingly, quantification of circulating thrombocytes in 6 day old nfe2 null zebrafish larvae showed no significant differences from wild type siblings. Finally, we performed colony forming assays on whole kidney marrow lysates to measure the ability of hematopoietic progenitors to differentiate into thrombocytes. Both mutant and wild type adults are capable of producing thrombocytic colonies in the presence of thrombopoietin and erythropoietin. We and others have shown that thrombocytes participate in the formation of induced thrombi upon laser-mediated endothelial injury in zebrafish embryos and larvae. We tested the functionality of nfe2-/- thrombocytes and were surprised to find that wild type and nfe2 null zebrafish larvae form fibrin- and thrombocyte-rich clots in response to endothelial injury at day of life 3 (venous circulation) and 6 (arterial circulation), respectively. Measurement of both the time to occlusion as well as the total number of thrombocytes adhering to the site of injury revealed no significant differences between wild type and nfe2-/- larvae. These data suggest that loss of Nfe2 results in a late block in thrombopoiesis with secondary expansion of thrombocytic precursors, both features that are consistent with mammals. Surprisingly, Nfe2 appears to be dispensable for early embryonic thrombocyte production and function. These results suggest parallels with erythropoiesis, including distinct primitive and definitive pathways of development. This includes the potential for a previously unknown Nfe2-independent pathway of embryonic thrombopoiesis. The long term homozygous mutant survival will also facilitate more in depth study of Nfe2 deficiency in vivo, and further investigation could lead to alternative methodologies for the enhancement of platelet production in vivo or ex vivo. Disclosures Zon: Fate, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Scholar Rock: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Marauder Therapeutics: Equity Ownership, Other: Founder.
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Li, You-Jun, Rachel R. Higgins, Brian J. Pak, Ramesh A. Shivdasani, Paul A. Ney, Michael Archer, and Yaacov Ben-David. "p45NFE2 Is a Negative Regulator of Erythroid Proliferation Which Contributes to the Progression of Friend Virus-Induced Erythroleukemias." Molecular and Cellular Biology 21, no. 1 (January 1, 2001): 73–80. http://dx.doi.org/10.1128/mcb.21.1.73-80.2001.
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ABSTRACT In previous studies, we identified a common site of retroviral integration designated Fli-2 in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia cell lines. Insertion of F-MuLV at the Fli-2 locus, which was associated with the loss of the second allele, resulted in the inactivation of the erythroid cell- and megakaryocyte-specific genep45 NFE2 . Frequent disruption ofp45 NFE2 due to proviral insertion suggests a role for this transcription factor in the progression of Friend virus-induced erythroleukemias. To assess this possibility, erythroleukemia was induced by F-MuLV inp45 NFE2 mutant mice. Sincep45 NFE2 homozygous mice mostly die at birth, erythroleukemia was induced in +/− and +/+ mice. We demonstrate that +/− mice succumb to the disease moderately but significantly faster than +/+ mice. In addition, the spleens of +/− mice were significantly larger than those of +/+ mice. Of the 37 tumors generated from the +/− and +/+ mice, 10 gave rise to cell lines, all of which were derived from +/− mice. Establishment in culture was associated with the loss of the remaining wild-typep45 NFE2 allele in 9 of 10 of these cell lines. The loss of a functional p45NFE2 in these cell lines was associated with a marked reduction in globin gene expression. Expression of wild-typep45 NFE2 in the nonproducer erythroleukemic cells resulted in reduced cell growth and restored the expression of globin genes. Similarly, the expression ofp45 NFE2 in these cells also slows tumor growth in vivo. These results indicate thatp45 NFE2 functions as an inhibitor of erythroid cell growth and that perturbation of its expression contributes to the progression of Friend erythroleukemia.
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Dou, Rui, Xiong Wang, and Jin Zhang. "Prognostic Value and Immune Infiltration Analysis of Nuclear Factor Erythroid-2 Family Members in Ovarian Cancer." BioMed Research International 2022 (January 11, 2022): 1–9. http://dx.doi.org/10.1155/2022/8672258.
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Ovarian cancer (OC) often presents at an advanced stage and is still one of the most frequent causes of gynecological cancer-related mortality worldwide. The nuclear factor erythroid-2 (NFE2) transcription factors include nuclear factor, erythroid 2 like 1 (NFE2L1), NFE2L2, and NFE2L3. NFE2 members bind to the antioxidant-response element (ARE) region and activate the expression of targeted genes. The distinct functions of NFE2 members in OC remain poorly elucidated. Several online bioinformatics databases were applied to determine gene expression, prognosis, mutations, and immune infiltration correlation in OC patients. NFE2L1 and NFE2L2 were decreased in OC, whereas NFE2L3 was increased. NFE2L2 and NFE2L3 were significantly correlated with the clinical stages of OC. High NFE2L1 level was significantly associated with short progression-free survival (PFS) in patients with OC ( HR = 1.18 , P = 0.021 ), while high NFE2L2 expression strongly correlated with long PFS ( HR = 0.77 , P = 0.00067 ). High NFE2L3 expression was associated with better overall survival and postprogression survival in OC. Functional analysis showed that NFE2 members mainly focused on transcription coactivator activities. Genetic alterations of NFE2 members were found in 13% of OC patients, and amplification ranked the top. The expression of NFE2 members was significantly correlated with immune infiltration of CD4+ T cells, CD8+ T cells, B cells, macrophages, and neutrophils in OC. Our study provides novel insights into the roles and prognostic potential of NFE2 family members in OC.
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Pratt, Stephen J., Anna Drejer, Helen Foott, Bruce Barut, Alison Brownlie, John Postlethwait, Yasutake Kato, Masayuki Yamamoto, and Leonard I. Zon. "Isolation and characterization of zebrafish NFE2." Physiological Genomics 11, no. 2 (October 29, 2002): 91–98. http://dx.doi.org/10.1152/physiolgenomics.00112.2001.
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Vertebrate hematopoiesis is regulated by distinct cell-specific transcription factors such as GATA-1 and SCL. Mammalian p45-NFE2 was characterized for its ability to bind the hypersensitive sites of the globin locus control region. NFE2 is a member of a cap’n’collar (CNC) and basic zipper (BZIP) superfamily that regulates gene transcription. It has been implicated in diverse processes such as globin gene expression, oxidative stress, and platelet lineage differentiation. Here, we have isolated the zebrafish ortholog of NFE2. The gene is highly homologous, particularly in the DNA-binding domain. Mapping the zebrafish NFE2 to linkage group 23 establishes a region of chromosomal synteny with human chromosome 12, further suggesting evolutionary conservation. During embryogenesis, the zebrafish gene is expressed specifically in erythroid cells and also in the developing ear. NFE2 expression is lacking in zebrafish mutants that have no hematopoietic cells. An analysis of the sauternes mutant, which carries a mutation in the ALAS-2 gene and thus has defective heme synthesis, demonstrates higher levels of NFE2 expression than normal. This further establishes the block to erythroid differentiation in the sauternes mutant. Our studies demonstrate conservation of the vertebrate genetic program for the erythroid lineage.
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Heuston, Elisabeth F., Jens Lichtenberg, Stacie M. Anderson, Vikram R. Paralkar, Cheryl Keller Capone, Ross C. Hardison, Mitchell J. Weiss, and David M. Bodine. "Differences In The Genome-Wide Epigenetic Signatures Of mRNA and Long Non-Coding RNA Genes In Mouse Erythroblasts and Megakaryocytes." Blood 122, no. 21 (November 15, 2013): 1198. http://dx.doi.org/10.1182/blood.v122.21.1198.1198.
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Abstract The ENCODE project has demonstrated that epigenetic signatures, including DNA methylation and transcription factor (TF) occupancy, define gene expression. However, ENCODE was constructed using static cells that were not capable of further differentiation. We hypothesize that specific epigenetic profiles are associated with erythroid and megakaryocytic differentiation. To test this hypothesis, we isolated primary erythroblasts (EBs) and megakaryocytes (Megs) from mouse bone marrow by flow cytometry and prepared: 1) DNA for genome-wide methylation analysis using MBD2 Methyl-Seq; 2) RNA for both RNA-Seq analysis and microarray analysis of novel and annotated lncRNA expression levels; and 3) chromatin for genome-wide chromatin immunoprecipitation (ChIP-Seq) analysis of occupancy by the TFs GATA1 and NFE2. We developed the web-based high-throughput sequencing tool suite SigSeeker (http://sigseeker.org) to predict regions of methylation and TF occupancy across the genome. High-confidence methylation, GATA1, and NFE2 profiles, represented by the intersection of two independent EB and Meg biological replicates, are shown in Table 1. Of the approximate 100,000 methylated regions in EBs and Megs, 45% were shared between the two cell types. Unlike methylation, GATA1 and NFE2 occupancy showed strong cell type-specific profiles, with most GATA1 occupied sites (79%) being EB-specific, and most NFE2 occupied sites (72%) being Meg-specific. While 26% of EB-specific GATA1 peaks were co-occupied by NFE2, co-occupancy by GATA1 and NFE2 in Megs was rare (0.6%). We developed a second web-based tool called SBR (http://sbrblood.msseeker.org) to correlate ChIP-Seq and Methyl-Seq profiles with RNA-Seq and lncRNA transcriptional data sets. Almost 95% of RefSeq (coding) genes with methylation in the promoter regions were not expressed. Fewer than 5% of methylated RefSeq promoters also had TF occupancy. Unlike promoters, the bodies of RefSeq genes had a high degree of overlap between methylation and TF binding. In EBs, 38% of RefSeq genes with GATA1 occupancy in the body were methylated. Of genes with this profile, 81% were transcriptionally silent. In Megs, 42% of RefSeq genes with NFE2 occupancy in the body were methylated. However, 80% of these Meg-specific genes were transcriptionally active. In contrast to RefSeq genes, lncRNA genes have a different signature. More than 85% of EB-expressed lncRNA promoters are methylated and ∼25% of these promoters are occupied by GATA1 and/or NFE2. Over 90% of EB-expressed lncRNA gene bodies occupied by GATA1 and/or NFE2 are methylated. In contrast less than 10% of Meg-expressed lncRNA promoters are methylated and ∼only 2% of these promoters are occupied by NFE2. However, 90% of Meg-expressed lncRNA gene bodies occupied by GATA1 and/or NFE2 are methylated. Ingenuity IPA analysis of the transcriptional profiles associated with different epigenetic signatures revealed differentially regulated cellular pathways. In EBs, GATA1 occupancy in the promoters of silent genes was associated with cardiovascular (p≤ 10-7) and nervous system development (p≤ 10-7). In Megs, NFE2 promoter occupancy was associated with active genes involved in nucleic acid metabolism (p≤ 10-3) and nervous system development (p≤ 10-5). Genes expressed in both EBs and Megs were involved in transcription (p≤ 10-6), cell cycle progression (p≤ 10-5), and decreased hypoplasia (p≤ 10-20). GATA1 and NFE2 co-occupied genes expressed in both EBs and Megs were associated with suppression of bone-related (p≤ 10-6) and neuron-related transcripts (p≤ 10-8). In summary, we show that TF occupancy and methylation significantly overlap in RefSeq gene bodies, but not in promoters. These profiles have revealed that GATA1 occupancy, independent of NFE2 co-occupancy, correlates with EB-specific transcriptional silencing, whereas Meg-specific transcriptional activation is associated with NFE2 occupancy. In contrast, over 90% active and TF-occupied lncRNA (both novel and previously annotated) gene bodies are methylated. These epigenetic correlations will be important for future studies assessing the regulation of mRNAs and lncRNAs. Disclosures: No relevant conflicts of interest to declare.
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Lee, Taunia D., Heping Yang, Janet Whang, and Shelly C. Lu. "Cloning and characterization of the human glutathione synthetase 5′-flanking region." Biochemical Journal 390, no. 2 (August 23, 2005): 521–28. http://dx.doi.org/10.1042/bj20050439.
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GSH synthesis occurs through a two-step enzymatic reaction driven by GCL (glutamate–cysteine ligase; made up of catalytic and modifying subunits) and GSS (glutathione synthetase). In humans, oxidative stress regulates GCL expression in an antioxidant response element-dependent manner via Nrf2 [NFE (nuclear factor erythroid)-related factor 2]. In the rat, GSS and GCL are regulated co-ordinately by oxidative stress, and induction of GSS further increases GSH synthetic capacity. Transcriptional regulation of the human GSS has not been examined. To address this, we have cloned and characterized a 2.2 kb 5′-flanking region of the human GSS. The transcriptional start site is located 80 nt upstream of the translation start site. The human GSS promoter efficiently drove luciferase expression in Chang cells. Overexpression of either Nrf1 or Nrf2 induced the GSS promoter activity by 130 and 168% respectively. Two regions homologous to the NFE2 motif are demonstrated to be important for basal expression of human GSS, as mutation of these sites reduced the promoter activity by 66%. Nrf1, Nrf2 and c-Jun binding to these NFE2 sites under basal conditions was demonstrated using chromatin immunoprecipitation assays. In summary, two NFE2 sites in the human GSS promoter play important roles in the basal expression of GSS and, similar to the GCL subunits, the human GSS gene expression is also regulated by Nrf2.
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Boas, Stephanie M., Kathlene L. Joyce, and Rita M. Cowell. "The NRF2-Dependent Transcriptional Regulation of Antioxidant Defense Pathways: Relevance for Cell Type-Specific Vulnerability to Neurodegeneration and Therapeutic Intervention." Antioxidants 11, no. 1 (December 21, 2021): 8. http://dx.doi.org/10.3390/antiox11010008.
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Oxidative stress has been implicated in the etiology and pathobiology of various neurodegenerative diseases. At baseline, the cells of the nervous system have the capability to regulate the genes for antioxidant defenses by engaging nuclear factor erythroid 2 (NFE2/NRF)-dependent transcriptional mechanisms, and a number of strategies have been proposed to activate these pathways to promote neuroprotection. Here, we briefly review the biology of the transcription factors of the NFE2/NRF family in the brain and provide evidence for the differential cellular localization of NFE2/NRF family members in the cells of the nervous system. We then discuss these findings in the context of the oxidative stress observed in two neurodegenerative diseases, Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), and present current strategies for activating NFE2/NRF-dependent transcription. Based on the expression of the NFE2/NRF family members in restricted populations of neurons and glia, we propose that, when designing strategies to engage these pathways for neuroprotection, the relative contributions of neuronal and non-neuronal cell types to the overall oxidative state of tissue should be considered, as well as the cell types which have the greatest intrinsic capacity for producing antioxidant enzymes.
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Marcault, Clemence, Lin-Pierre Zhao, Rafael Daltro De Oliveira, Juliette Soret, Nicolas Gauthier, Emmanuelle Verger, Nabih Maslah, et al. "NFE2 Mutations Impact AML Transformation and Overall Survival in Patients with Myeloproliferative Neoplasms (MPN)." Blood 136, Supplement 1 (November 5, 2020): 36. http://dx.doi.org/10.1182/blood-2020-136177.
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Introduction: MPN are a heterogeneous group of chronic hematological malignancies often resulting from a combination of a driver gene mutation (JAK2, MPL or CALR) and a variety of somatic mutations harboring diverse prognosis values. A subset of MPN patients carry somatic mutations in the hematopoietic transcription factor NFE2 (nuclear factor erythroid 2) resulting in a functionally enhanced truncated form of NFE2 (Jutzi JS et al., JEM, 2013). Moreover, epigenetically induced overexpression of NFE2 has recently been reported in the majority of MPN patients (Peeken JC et al., Blood, 2018). In transgenic murine models, NFE2 overexpression results in an MPN phenotype (thrombocytosis, leukocytosis, EPO-independent colony formation, characteristic bone marrow histology and expansion of stem and progenitor compartments) and has recently been shown to predispose to the acquisition of additional genetic abnormalities and subsequent leukemic transformation (Kaufmann KB et al., JEM, 2012) (Jutzi JS et al., Blood, 2019). However, clinical impact of NFE2 mutations in MPN patients remains unknown. The aim of this study was to evaluate the phenotypic characteristics and prognostic impact of NFE2 somatic mutations in a large mono-centric cohort of MPN patients. Methods: A total of 1243 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and May 2020. This study included 707 of them in whom a next-generation sequencing (NGS) molecular analysis targeting 36 myeloid genes was performed at diagnosis and/or during follow-up. Clinical and biological characteristics at time of diagnosis and follow-up were collected from medical charts and electronic medical records. Statistical analyses were performed using the STATA software (STATA 15.0 Corporation, College Station, TX). Results: In our cohort, 411 patients presented with polycythemia vera (PV), 577 with essential thrombocythemia (ET), 184 with primary or pre-fibrotic myelofibrosis (PMF), 59 with unclassified MPN and 12 with MDS/MPN. Median age at diagnosis was 51 years [40-63]. 73.1% patients had a JAK2V617F mutation, 14.1% a CALR mutation and 3.3% a MPL mutation. Overall, 64 (9.05%) patients harbored a NFE2 mutation with a variant allelic frequency (VAF) ≥ 0.5% and 36 had a VAF ≥ 5%, the latest were considered as NFE2 mutated for the rest of the study as VAF <5% may refer to a minor clone without clinical relevance. NFE2 mutations were present in 7.3%, 5.3% and 3.6% of PV, PMF and ET patients respectively. No significant association between the presence of NFE2 mutation and clinical/molecular MPN characteristics (driver mutation, constitutional symptoms, splenomegaly, blood counts, cytogenetic and other molecular features) was observed using a logistic regression association model. Median follow-up was 103.8 months, IQR [47.2; 175.6]. In terms of response to therapy, 52.8% of patients achieved complete response, complete hematological response or clinical improvement in NFE2 mutated vs 61.7% in non-mutated patients (p= 0.026). Interestingly, presence of a NFE2 mutation (HR 9.92, 95%CI[3.21; 30.64], p< 0.001), age at diagnosis (HR 1.09, 95%CI[1.05; 1.12], p< 0.001), PMF subtype (HR 6.92, 95%CI[2.81; 17.06], p < 0.001) and high-risk mutations (ASXL1, EZH2, SRSF2, IDH1/2 and U2AF1) (HR 2.45, 95%CI[1.14; 5.28], p=0.021) were independently associated with AML/MDS transformation free survival (TFS) in a COX regression multivariate analysis (Figure A). Presence of a NFE2 mutation was also independently associated with overall survival (OS) (HR 9.37, 95%CI [4.18; 21.03], p<0.001) (Figure B). Median TFS were 216.1 months and not reached, while median OS were 144.2 months and not reached for NFE2 mutated and non-mutated patients, respectively. No difference was observed in terms of thrombo-hemorrhagic events (HR 0.73; 95%CI [0.10; 5.21], p=0.752) and secondary myelofibrosis free survivals (HR 0.67; 95%CI [0.09; 4.87], p=0.693). Conclusion: In this retrospective study we show that presence of NFE2 mutations with a VAF ≥5% is independently associated with an increased risk of leukemic transformation and shorter overall survival. These findings are in line with recently reported animal models and suggest that NFE2 mutations screening should be routinely performed in MPN patients. Disclosures Rea: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead Foundation: Research Funding.
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Zhang, Di, Sadahiro Iwabuchi, Tomohisa Baba, Shin-ichi Hashimoto, Naofumi Mukaida, and So-ichiro Sasaki. "Involvement of a Transcription factor, Nfe2, in Breast Cancer Metastasis to Bone." Cancers 12, no. 10 (October 16, 2020): 3003. http://dx.doi.org/10.3390/cancers12103003.
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Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, which deteriorates the life expectancy of this patient cohort. In order to develop a novel type of therapy for bone metastasis, we established 4T1.3 clone with a high capacity to metastasize to bone after orthotopic injection, from a murine TNBC cell line, 4T1.0. To elucidate the molecular mechanism underlying a high growth ability of 4T1.3 in a bone cavity, we searched for a novel candidate molecule with a focus on a transcription factor whose expression was selectively enhanced in a bone cavity. Comprehensive gene expression analysis detected enhanced Nfe2 mRNA expression in 4T1.3 grown in a bone cavity, compared with in vitro culture conditions. Moreover, Nfe2 gene transduction into 4T1.0 cells enhanced their capability to form intraosseous tumors. Moreover, Nfe2 shRNA treatment reduced tumor formation arising from intraosseous injection of 4T1.3 clone as well as another mouse TNBC-derived TS/A.3 clone with an augmented intraosseous tumor formation ability. Furthermore, NFE2 expression was associated with in vitro growth advantages of these TNBC cell lines under hypoxic condition, which mimics the bone microenvironment, as well as Wnt pathway activation. These observations suggest that NFE2 can potentially contribute to breast cancer cell survival in the bone microenvironment.
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Jutzi, Jonas Samuel, Titiksha Basu, Maximilian Pellmann, Sandra Kaiser, Doris Steinemann, Mathijs A. Sanders, Adil S. A. Hinai, et al. "Altered NFE2 activity predisposes to leukemic transformation and myelosarcoma with AML-specific aberrations." Blood 133, no. 16 (April 18, 2019): 1766–77. http://dx.doi.org/10.1182/blood-2018-09-875047.
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Abstract In acute myeloid leukemia (AML), acquired genetic aberrations carry prognostic implications and guide therapeutic decisions. Clinical algorithms have been improved by the incorporation of novel aberrations. Here, we report the presence and functional characterization of mutations in the transcription factor NFE2 in patients with AML and in a patient with myelosarcoma. We previously described NFE2 mutations in patients with myeloproliferative neoplasms and demonstrated that expression of mutant NFE2 in mice causes a myeloproliferative phenotype. Now, we show that, during follow-up, 34% of these mice transform to leukemia presenting with or without concomitant myelosarcomas, or develop isolated myelosarcomas. These myelosarcomas and leukemias acquired AML-specific alterations, including the murine equivalent of trisomy 8, loss of the AML commonly deleted region on chromosome 5q, and mutations in the tumor suppressor Trp53. Our data show that mutations in NFE2 predispose to the acquisition of secondary changes promoting the development of myelosarcoma and/or AML.
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Loyd, Melanie R., Yasuhiro Okamoto, Mindy S. Randall, and Paul A. Ney. "Role of AP1/NFE2 binding sites in endogenous α-globin gene transcription." Blood 102, no. 12 (December 1, 2003): 4223–28. http://dx.doi.org/10.1182/blood-2003-02-0574.
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Abstract High-level α-globin expression depends on cis-acting regulatory sequences located far upstream of the α-globin cluster. Sequences that contain the α-globin positive regulatory element (PRE) activate α-globin expression in transgenic mice. The α-globin PRE contains a pair of composite binding sites for the transcription factors activating protein 1 and nuclear factor erythroid 2 (AP1/NFE2). To determine the role of these binding sites in α-globin gene transcription, we mutated the AP1/NFE2 sites in the α-globin PRE in mice. We replaced the AP1/NFE2 sites with a neomycin resistance gene (neo) that is flanked by LoxP sites (floxed). Mice with this mutation exhibited increased embryonic death and α-thalassemia intermedia. Next, we removed the neo gene by Cre-mediated recombination, leaving a single LoxP site in place of the AP1/NFE2 sites. These mice were phenotypically normal. However, α-globin expression, measured by allele-specific RNA polymerase chain reaction (PCR), was decreased 25%. We examined the role of the hematopoietic-restricted transcription factor p45Nfe2 in activating expression through these sites and found that it is not required. Thus, we have demonstrated that AP1/NFE2 binding sites in the murine α-globin PRE contribute to long-range α-globin gene activation. The proteins that mediate this effect remain to be determined. (Blood. 2003;102:4223-4228)
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Crispino, John D. "JAK2 and JMJD1C activate NFE2 in MPNs." Blood 131, no. 18 (May 3, 2018): 1998–99. http://dx.doi.org/10.1182/blood-2018-03-839779.
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Amaru, Ariel, Katia Todoerti, Anna Pellicioli, Luca Donadoni, Giacomo Tuana, Olga Pedrini, Guido Finazzi, et al. "The HDAC INHIBITOR ITF2357 MODULATES KEY HEMATOPOIETIC GENES in JAK2V617F CELLS From MYELOPROLIFERATIVE Neoplasm PATIENTS." Blood 116, no. 21 (November 19, 2010): 797. http://dx.doi.org/10.1182/blood.v116.21.797.797.
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Abstract Abstract 797 We have previously shown that the pan-HDAC inhibitor ITF2357 has strong cytotoxic activity against cells from patients with myeloproliferative neoplasms (MPN) bearing JAK2 mutation at position 617. Indeed ITF2357 inhibited colony growth of JAK2V617F positive cells at doses 5–10 fold lower than those required to block JAK2 wild type cells. We have therefore investigated here the molecular mechanism of this effect. Three cell lines homozygotes (HEL, UKE1) or heterozygotes (SET2) for the JAK2V617F mutation were used along with cell lines bearing JAK2 wild type (K562 and KG1). We confirmed the higher sensitivity of mutated with respect to unmutated cell lines in colony formation assay (mean IC50 42 nM versus 179 nM) and alamar blue assay (mean IC50 84 nM vs 325 nM, respectively). In proliferation assays measuring number of live and dead cells at different time points, we observed that 100 nM ITF2357 blocked the proliferation of both JAK2 mutated and unmutated cell lines to a similar extent, with mean inhibition of 31–69% at 72 hours, but induced apoptosis more efficiently in JAK2 mutated (mean 34%) versus unmutated cells (mean 2%). By cell cycle analysis we could show a block in G1 phase of cell cycle in JAK2V617F cells treated with 100 nM drug. In order to unravel the mechanism of specific inhibition of JAK2 mutated cells by ITF2357, we first investigated expression of HDAC isoforms in the different cell lines. We could detect HDAC1, HDAC2 and HDAC3 proteins in Western blots but these were not differentially expressed in a panel of 3 JAK2 mutated and 3 wild type cell lines. We then set out to analyse the molecular mechanism of action of ITF2357 by global gene expression analysis. Using the Rank Product method with a false positive prediction (pfp) of 0.05 and a 2 fold change cut off parameters, we observed 716 and 863 genes modulated at 6 hours by 250 nM ITF2357 in HEL and UKE-1 cell lines, respectively; 293 of these, (179 up- and 114 down-regulated), were common between both cell lines and 10 were subsequently validated by Q-RT-PCR. Among differentially expressed genes, a number are known to play an important role in the control of proliferation and /or apoptosis, most notably APAF1, BCL2L11, CCNG2, NFKB2, MXD1 and TP53INP1, while additional 6 genes (C-MYB, A-MYB, TAL1, NFE2, MLF1, NOTCH2) are involved in the control of hematopoietic differentiation. Of particular interest is NFE2, which was down modulated 2.7 fold by ITF2357 at 6 hours at the RNA level and by about 2 fold at 24 hours at the protein level. NFE2 has been reported to be hyperexpressed in JAK2V617 MPN patients. We also showed that ITF2357 downmodulated NFE2 expression 2 fold also in CD34+ cells purified from these patients. Given the accepted role of NFE2 in the control of erythroid progenitor cell proliferation and differentiation, and its enhanced expression in MPN patients, our data suggest that NFE2 down-regulation by ITF2357 may at least partially explain the drug effect on growth of MPN progenitor cells. The regulation of NFE2 expression and that of other hematopoietic transcription factors and regulatory proteins in response to ITF2357 is under investigation in our laboratory and data will be presented. Disclosures: Fossati: Italfarmaco SpA: Employment. Rambaldi:Italfarmaco SpA: Research Funding. Golay:Italfarmaco SpA: Research Funding.
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Kashif, M., A. Hellweg, M. Thati, S. Herzog, I. Vinnikov, K. Shahzad, P. P. Nawroth, and B. Isermann. "O17 The transcription factor NFE2 regulates trophoblast differentiation." Thrombosis Research 123 (January 2009): S136. http://dx.doi.org/10.1016/s0049-3848(09)70042-8.
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Miller, JL, CE Walsh, PA Ney, RJ Samulski, and AW Nienhuis. "Single-copy transduction and expression of human gamma-globin in K562 erythroleukemia cells using recombinant adeno-associated virus vectors: the effect of mutations in NF-E2 and GATA-1 binding motifs within the hypersensitivity site 2 enhancer [published erratum appears in Blood 1995 Feb 1;85(3):862]." Blood 82, no. 6 (September 15, 1993): 1900–1906. http://dx.doi.org/10.1182/blood.v82.6.1900.1900.
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Abstract The use of recombinant adeno-associated virus (rAAV) vectors provides a new strategy to investigate the role of specific regulatory elements and trans-acting factors in globin gene expression. We linked hypersensitivity site 2 (HS2) from the locus control region (LCR) to a A gamma-globin gene (A gamma*) mutationally marked to allow its transcript to be distinguished from endogenous gamma-globin mRNA. The vector also contains the phosphotransferase gene that confers resistance to neomycin (NeoR). HS2 region mutations within the NF-E2 motifs prevented NF-E2 binding while preserving AP-1 binding. Another set in the GATA-1 motif prevented binding of the factor. Several NeoR K562 clones containing a single unrearranged RAAV genome with the A gamma* gene linked to the native HS2 core fragment (WT), mutant NF-E2 HS2 (mut-NFE2), mutant GATA-1 HS2 (mut-GATA1), or no HS [(-)HS] were identified. In uninduced K562 cells, mut-NFE2 clones expressed A gamma* mRNA at the same level as the WT clones, compared with a lack of A gamma* signal in the (-)HS2 clones. However, hemin induction of mut- NFE2 clones did not result in an increase in the A gamma* signal above the level seen in uninduced cells. Mut-GATA1 clones expressed the A gamma* mRNA at the same level as WT clones in both uninduced and induced cells. Thus, GATA-1 binding to this site does not appear to be required for the enhancing function of HS2 in this context. This single- copy rAAV transduction model is useful for evaluating the effects of specific mutations in regulatory elements on the transcription of linked genes.
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Miller, JL, CE Walsh, PA Ney, RJ Samulski, and AW Nienhuis. "Single-copy transduction and expression of human gamma-globin in K562 erythroleukemia cells using recombinant adeno-associated virus vectors: the effect of mutations in NF-E2 and GATA-1 binding motifs within the hypersensitivity site 2 enhancer [published erratum appears in Blood 1995 Feb 1;85(3):862]." Blood 82, no. 6 (September 15, 1993): 1900–1906. http://dx.doi.org/10.1182/blood.v82.6.1900.bloodjournal8261900.
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The use of recombinant adeno-associated virus (rAAV) vectors provides a new strategy to investigate the role of specific regulatory elements and trans-acting factors in globin gene expression. We linked hypersensitivity site 2 (HS2) from the locus control region (LCR) to a A gamma-globin gene (A gamma*) mutationally marked to allow its transcript to be distinguished from endogenous gamma-globin mRNA. The vector also contains the phosphotransferase gene that confers resistance to neomycin (NeoR). HS2 region mutations within the NF-E2 motifs prevented NF-E2 binding while preserving AP-1 binding. Another set in the GATA-1 motif prevented binding of the factor. Several NeoR K562 clones containing a single unrearranged RAAV genome with the A gamma* gene linked to the native HS2 core fragment (WT), mutant NF-E2 HS2 (mut-NFE2), mutant GATA-1 HS2 (mut-GATA1), or no HS [(-)HS] were identified. In uninduced K562 cells, mut-NFE2 clones expressed A gamma* mRNA at the same level as the WT clones, compared with a lack of A gamma* signal in the (-)HS2 clones. However, hemin induction of mut- NFE2 clones did not result in an increase in the A gamma* signal above the level seen in uninduced cells. Mut-GATA1 clones expressed the A gamma* mRNA at the same level as WT clones in both uninduced and induced cells. Thus, GATA-1 binding to this site does not appear to be required for the enhancing function of HS2 in this context. This single- copy rAAV transduction model is useful for evaluating the effects of specific mutations in regulatory elements on the transcription of linked genes.
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Meechoowas, Ekarat, Parida Jampeerung, Kanit Tapasa, and Tepiwan Jitwatcharakomol. "The Decolorizing of High Iron Containing Soda-Lime Silicate Glass by Annealing Process." Key Engineering Materials 702 (July 2016): 130–34. http://dx.doi.org/10.4028/www.scientific.net/kem.702.130.
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The tableware soda-lime silicate glasses, contained with 0.06 wt% of iron oxide, which were annealed at different times and temperatures, were investigated by UV-Vis spectroscopy. The glasses were produced from high iron sand. The iron content was twice as high in the glasses as it is in normal tableware glasses. The redox reaction of iron around glass transition temperature, Fe2+(green) ↔ Fe3+(yellow), was found in the annealing process, according to the redox reaction of iron with polyvalent ions in the glass, nFe3+ + Ma+ ↔ nFe2+ + M(a+-n) where M is the polyvalent ion in glass. In this study, the glasses were prepared by melting in a platinum crucible. After casting, they were annealed with variable times and temperatures. The results of color in CIE L*a*b* system and Fe2+/Fe3+ ratio of glasses showed the effect of the annealing process on the redox reaction of iron. The decolorizing was found during the annealing process. The results of this work led to the method for controlling the effect of iron oxide in the glass and the possibility to use high iron sand to produce tableware glasses.Tableware glass, Iron oxide, Redox reaction, Decolorizing
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Zhang, Bing, and Tao Sun. "Transcription Factors That Regulate the Pathogenesis of Ulcerative Colitis." BioMed Research International 2020 (August 25, 2020): 1–9. http://dx.doi.org/10.1155/2020/7402657.
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Ulcerative colitis (UC) is one of the inflammatory bowel diseases (IBD) characterized by occurrence in the rectum and sigmoid colon of young adults. However, the functional roles of transcription factors (TFs) and their regulating target genes and pathways are not fully known in ulcerative colitis (UC). In this study, we collected gene expression data to identify differentially expressed TFs (DETFs). We found that differentially expressed genes (DEGs) were significantly enriched in the target genes of HOXA2, IKZF1, KLF2, XBP1, EGR2, ETV7, BACH2, CBFA2T3, HLF, and NFE2. TFs including BACH2, CBFA2T3, EGR2, ETV7, NFE2, and XBP1, and their target genes were significantly enriched in signaling by interleukins. BACH2 target genes were enriched in estrogen receptor- (ESR-) mediated signaling and nongenomic estrogen signaling. Furthermore, to clarify the functional roles of immune cells on the UC pathogenesis, we estimated the immune cell proportions in all the samples. The accumulated effector CD8 and reduced proportion of naïve CD4 might be responsible for the adaptive immune response in UC. The accumulation of plasma in UC might be associated with increased gut permeability. In summary, we present a systematic study of the TFs by analyzing the DETFs, their regulating target genes and pathways, and immune cells. These findings might improve our understanding of the TFs in the pathogenesis of UC.
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Rheinemann, L., T. S. Seeger, J. Wehrle, and H. L. Pahl. "NFE2 regulates transcription of multiple enzymes in the heme biosynthesis pathway." Haematologica 99, no. 10 (June 20, 2014): e208-e210. http://dx.doi.org/10.3324/haematol.2014.106393.
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Kashif, Muhammed, Andrea Hellwig, Said Hashemolhosseini, Varun Kumar, Fabian Bock, Hongjie Wang, Khurrum Shahzad, et al. "Nuclear Factor Erythroid-derived 2 (Nfe2) Regulates JunD DNA-binding Activity via Acetylation." Journal of Biological Chemistry 287, no. 8 (December 15, 2011): 5400–5411. http://dx.doi.org/10.1074/jbc.m111.289801.
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Fallatah, Weam, Ronika De, David Burks, Rajeev K. Azad, and Pudur Jagadeeswaran. "Analysis of transcribed sequences from young and mature zebrafish thrombocytes." PLOS ONE 17, no. 3 (March 23, 2022): e0264776. http://dx.doi.org/10.1371/journal.pone.0264776.
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The zebrafish is an excellent model system to study thrombocyte function and development. Due to the difficulties in separating young and mature thrombocytes, comparative transcriptomics between these two cell types has not been performed. It is important to study these differences in order to understand the mechanism of thrombocyte maturation. Here, we performed single-cell RNA sequencing of the young and mature zebrafish thrombocytes and compared the two datasets for young and mature thrombocyte transcripts. We found a total of 9143 genes expressed cumulatively in both young and mature thrombocytes, and among these, 72% of zebrafish thrombocyte-expressed genes have human orthologs according to the Ensembl human genome annotation. We also found 397 uniquely expressed genes in young and 2153 uniquely expressed genes in mature thrombocytes. Of these 397 and 2153 genes, 272 and 1620 corresponded to human orthologous genes, respectively. Of all genes expressed in both young and mature thrombocytes, 4224 have been reported to be expressed in human megakaryocytes, and 1603 were found in platelets. Among these orthologs, 156 transcription factor transcripts in thrombocytes were found in megakaryocytes and 60 transcription factor transcripts were found in platelets including a few already known factors such as Nfe2 and Nfe212a (related to Nfe2) that are present in both megakaryocytes, and platelets. These results indicate that thrombocytes have more megakaryocyte features and since platelets are megakaryocyte fragments, platelets also appear to be thrombocyte equivalents. In conclusion, our study delineates the differential gene expression patterns of young and mature thrombocytes, highlighting the processes regulating thrombocyte maturation. Future knockdown studies of these young and mature thrombocyte-specific genes are feasible and will provide the basis for understanding megakaryocyte maturation.
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Hormaeche, Itsaso, Kim L. Rice, Arthur Zelent, Melanie J. McConnell, and Jonathan D. Licht. "PLZF-RARα Utilizes the Histone Methyl Transferase G9a/GLP and the Histone Demethylase LSD1 to Repress RARα Target Genes and Block Myeloid Differentiation." Blood 112, no. 11 (November 16, 2008): 198. http://dx.doi.org/10.1182/blood.v112.11.198.198.
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Abstract As a result of the t(11;17) translocation in retinoic acid resistant subtype of acute promyelocytic leukemia (APL), the transcriptional repression domains of the Promyelocytic Leukemia Zinc Finger protein (PLZF) are fused to the ligand binding and DNA binding domains of the Retinoic Acid Receptor α (RARα). The expression of PLZF-RARα as well as the reciprocal RARα-PLZF protein both appear to contribute to leukemogenesis. While the mode of action of PML-RARα has been studied in detail, less is known about transcriptional repression mediated by PLZF-RARα. We and others previously showed an important role of histone deacetylases in PLZF and PLZF-RARα mediated gene repression. We now find that expression of PLZF-RARα also modulates gene expression through changes in the state of histone methylation at target promoters. PLZF-RARα co-precipitated in vivo with endogenous G9a, a histone methyl transferase responsible for the mono and di-methylation of euchromatic histone 3 lysine tail residue 9 (H3K9me1/2), a covalent modification associated with gene repression. Deletion analysis of the PLZF-RARα fusion protein showed that the BTB/POZ domain of PLZF fused to RARα was sufficient to mediate this interaction. PLZF-RARα also bound in vivo to LSD1, a histone demethylase that removes methyl groups from mono or di-methylated Histone 3 lysine 4 (H3K4me1/2), a change generally associated with gene repression. As with G9a the BTB/POZ domain of PLZF was implicated in binding to LSD1. Co-precipitation experiments showed a robust interaction between PLZF-RARα and G9a and LSD1 while RARα, PML-RARα and NPM-RARα bound much more weakly, suggesting that the interaction with these histone modifying enzymes may be a mechanism relatively specific to t(11;17)-associated APL. To identify genes modulated by PLZF-RARα and determine how PLZF-RARα affects the chromatin of such genes we induced expression of PLZF-RARα in a U937 tetracycline-regulated system. PLZF-RARα directly repressed known RARα target genes such as NFE2, PRAM1 and C/EBPε. As a result of PLZF-RARα expression, U937T cells were blocked in differentiation characterized by decreased expression of the myeloid cell surface markers CD11b, CD14 and CD33. Chromatin immunoprecipitation experiments in this cell line showed that PLZF-RARα expression was associated with an increase in H3K9me1/me2 at the NFE2, PRAM1 and C/EBPε promoters. Knockdown of endogenous G9a by shRNA transduction reversed transcriptional repression mediated by the fusion protein on all three promoters. Both results are consistent with the presence of G9a in PLZF-RARα transcriptional complex. By contrast, the H3K4 methylation changes in response to PLZF-RARα were promoter specific and complex: while NFE2 exhibited a decrease in H3K4me1/2, consistent with the recruitment of LSD1 and demethylation, PRAM1 and C/EBPε showed an increase in these two modifications. Inhibition of LSD1 by tranylcypromine treatment as well as knockdown of LSD1 by shRNA only reverted PLZF-RARα repression of NFE2. PLZF-RARα recruitment to all three genes was associated with a decrease in H3K4trimethylation, a modification only accomplished by jumanji-class histone demethylases. Consistent with the biochemical information, knockdown of G9a or its heterodimeric partner GLP, showed a strong biological phenotype, reverting the block in myeloid differentiation caused by PLZF-RARα as measured by the expression of the myeloid cell surface markers CD11b and CD14. Depletion of LSD1 only modestly interfered with the differentiation block mediated by the fusion protein. Gene regulation by PLZF-RARα is associated with a complex set of chromatin changes mediated by a combination of histone deacetylases, methyl transferase and demethylases. All three classes of enzymes may represent therapeutic targets in t(11;17)-APL.
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Gasiorek, Jadwiga J., and Volker Blank. "Regulation and function of the NFE2 transcription factor in hematopoietic and non-hematopoietic cells." Cellular and Molecular Life Sciences 72, no. 12 (February 27, 2015): 2323–35. http://dx.doi.org/10.1007/s00018-015-1866-6.
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Opatz, Sabrina, Klaus H. Metzeler, Tobias Herold, Sebastian Vosberg, Kathrin Bräundl, Bianka Ksienzyk, Nikola P. Konstandin, et al. "The Mutatome of CBFB/MYH11-rearranged Acute Myeloid Leukemia (AML)." Blood 124, no. 21 (December 6, 2014): 14. http://dx.doi.org/10.1182/blood.v124.21.14.14.
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Abstract The fusion gene CBFB/MYH11 results from a pericentric inversion of chromosome 16, inv(16)(p13.1q22), or less commonly from a t(16;16)(p13.1;q22). This rearrangement is found in 6-8% of adult de novo AML cases and associated with favourable prognosis. Physiologically, CBFB binds to RUNX1 forming the core binding factor (CBF), which is a transcription factor essential for normal hematopoiesis and myeloid development. By disrupting transcription factor activity of CBF, the CBFB/MYH11 fusion protein causes repression of the CBF-dependent target genes resulting in a block of differentiation. Since expression of CBFB/MYH11 alone is not sufficient to cause leukemia it is likely that additional mutations are required for malignant transformation. To systematically identify non-silent mutations, which may collaborate with CBFB/MYH11 during leukemogenesis, we performed whole exome sequencing (WES) of 9 adult AML samples with inv(16) or t(16;16) and matched remission samples. Using this approach, we found 4-11 leukemia-specific sequence variants per patient (median: 6 mutations). These include mutations in genes known to cooperate with CBFB/MYH11 [e.g. NRAS (n=4), KRAS (n=4), FLT3 (n=2), KIT (n=1)] as well as in genes, which have not been described as mutated in AML so far (e.g. ZFHX4, NFE2). To test for recurrent mutations in selected genes, we designed a custom targeted resequencing assay (Haloplex, Agilent), comprising candidate genes from exome sequencing, as well as genes known to be recurrently mutated in AML (129 genes, 396.45 kbp total target sequence). We performed targeted deep amplicon sequencing on the diagnostic samples from 68 CBFB/MYH11-rearranged AML patients with a median read depth of 645. The results are summarized in Figure 1. Twenty-six genes were found mutated in at least 2 patients. The mutation frequencies of NRAS (35%), KRAS (21%), FLT3 (27%), KIT (22%) and WT1 (9%) were similar to previous reports. In addition, we found recurrent mutations with frequencies of above 5% in FAT1 (6%), PTPN11 (6%), NFE2 (6%) and ZFHX4 (6%). Recently, acquired NFE2 (Nuclear Factor, Erythroid-Derived 2) mutations were described in 2-3% of myeloproliferative neoplasms (MPN) cases. These truncating NFE2 mutations confer a proliferative advantage (Jutzi et al., 2013, JEM). ZFHX4 (Zinc Finger Homeobox 4) is required for the maintenance of tumor initiating cells in glioblastoma (Chudnovsky et al., 2014, Cell Rep). In 59% (40/68) of CBFB/MYH11-rearranged patients, more than one additional mutation was identified, but each of them at a distinct variant allele-frequency, indicating clonal heterogeneity. Recurrent mutations described in RUNX1/RUNX1T1-rearranged leukemia (Krauth et al., 2014, Leukemia, n= 139 patients, Micol et al., 2014, Blood, n= 110 patients) affecting genes such as IDH1/2 (4%), JAK2 (3%), ASXL1 (12%) and the recently described ASXL2 (23%) mutation were not found in our patients with CBFB/MYH11-rearranged CBF leukemia or considerably underrepresented (IDH1/2 0%, JAK2 0%, ASXL1 3%, ASXL2 0%). Commonly mutated genes in CBF leukemia like RAS-genes and FLT3 could be detected at higher frequency in our CBFB/MYH11 cohort (RAS-genes: 56% vs. 17%, FLT3: 27 vs. 13%), whereas KIT mutations occur in similar frequency (22% vs. 17-32%). Furthermore, we performed custom targeted resequencing in corresponding relapse samples from 7 patients with inv(16) in order to assess the clonal evolution. Surprisingly, all mutations in kinase genes [NRAS (n=1), KIT (n=2), FLT3 (n=3)] detected in 6 out of 7 cases at diagnosis were lost at relapse. Of note, one of these patients acquired mutations in WT1 and ZFHX4 and another patient acquired a CBL mutation at relapse. Taken together, our findings suggest that the mutatome of CBFB/MYH11-rearranged AML is genetically complex with co-existence of different subclones at diagnosis. Mutations in kinase genes such as NRAS, KIT, FLT3 seem to be unstable during disease progression and the actual driver of relapse remains elusive in many cases. Figure 1: Frequency distribution of mutations in 68 cases of CBFB/MYH11-rearranged AML Figure 1:. Frequency distribution of mutations in 68 cases of CBFB/MYH11-rearranged AML Disclosures No relevant conflicts of interest to declare.
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Kashif, M., T. Madhusudhan, S. U. E. Herzog, I. Vinnikov, S. Huntscha, P. P. Nawroth, and B. Isermann. "42 Absence of the transcription factor NFE2 impairs placental labyrinthine layer development during late midgestation." Thrombosis Research 119 (January 2007): S108. http://dx.doi.org/10.1016/s0049-3848(07)70087-7.
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Bae, Myoung Nam, Min Seok Choi, Sang-hoon Eum, Eun Nim Kim, Ji Hee Lim, Min Young Kim, Tae Hyun Ban, et al. "Age-related Changes in the Sirtuin1-NFE2-related Factor 2 Signaling System in the Kidney." Korean Journal of Medicine 92, no. 1 (February 1, 2017): 53–61. http://dx.doi.org/10.3904/kjm.2017.92.1.53.
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Bae, Myoung Nam, Min Seok Choi, Sang-hoon Eum, Eun Nim Kim, Ji Hee Lim, Min Young Kim, Tae Hyun Ban, et al. "Age-related Changes in the Sirtuin1-NFE2-related Factor 2 Signaling System in the Kidney." Korean Journal of Medicine 92, no. 2 (April 1, 2017): 224. http://dx.doi.org/10.3904/kjm.2017.92.1.53.e1.
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Aumann, Konrad, Martin Werner, and Heike L. Pahl. "Immunohistochemical staining of transcription factor NFE2 for the discrimination of primary myelofibrosis from essential thrombocythemia." Human Pathology 53 (July 2016): 195–96. http://dx.doi.org/10.1016/j.humpath.2016.02.024.
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Siegwart, Laura C., Sven Schwemmers, Julius Wehrle, Christoph Koellerer, Thalia Seeger, Albert Gründer, and Heike L. Pahl. "The transcription factor NFE2 enhances expression of the hematopoietic master regulators SCL/TAL1 and GATA2." Experimental Hematology 87 (July 2020): 42–47. http://dx.doi.org/10.1016/j.exphem.2020.06.004.
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Keefer, Jeffrey R., Shirley H. Purvis, George J. Dover, and Kirby D. Smith. "Analysis of the X-Linked F-Cell Production Locus." Blood 106, no. 11 (November 16, 2005): 3178. http://dx.doi.org/10.1182/blood.v106.11.3178.3178.
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Abstract This laboratory has previously identified a locus on the X chromosome at Xp22.2–22.3 (F-cell production locus or FCP) that is responsible for approximately 40% of the genetic variability in F-cell number in patients with sickle cell disease (SCD). We have re-examined the association of this region with F-cell production by multipoint linkage analysis. We have confirmed linkage to Xp22.2–22.3 and refined the candidate locus to a region of approximately 3 cM, between markers DXS452 and DXS410, with a maximum LOD score of 3.315. Linkage to a more extended region of 11 cM with an average LOD score of 1.5 could not be excluded. In an effort to identify candidate genes within this region that influence F-cell production, we screened known genes within this region for transcription factor binding sites that had relevance to HbF production. We first searched for CREB binding sites given the involvement of cAMP in of HbF induction in CD34 cells recently identified by this laboratory. Of the 15 ESTs containing CREB sequences, several also had binding sites for NFE2 or NFE2-like transcription factors. We examined 4 genes, 3 within the refined candidate locus (KIAA1280, TBL1X, and KAL1) and one in the more extended locus region (EGFL6) for expression levels within pedigrees of known F-cell phenotypes. Results indicate that, within families, a reduced level of KIAA1280 message is associated with high F-cell phenotypes in lymphoblastoid cells from patients with sickle cell anemia. The other genes examined had no such correlation. KIAA1280, also designated BMO42 is a gene of unknown function that is expressed in bone marrow. The predicted protein contains a region homologous to a conserved protein kinase C domain. While not yet definitive, these studies provide the first suggestive evidence for a candidate gene within the FCP locus. Further studies will attempt to define the function of this gene and explore it’s involvement in F-cell regulation.
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Yin, Jun, Wei Liu, Yan Kai, Wan Yao Wang, and Liang Liang. "Study on Hair Dyeing Wastewater by Fenton Oxidation Method." Applied Mechanics and Materials 522-524 (February 2014): 168–71. http://dx.doi.org/10.4028/www.scientific.net/amm.522-524.168.
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Hair dyeing wastewater is produced in coloring process. Its composition is complicated,in which contains a large number of organic pollutants and high color. Hair dyeing wastewater treatment can be effectively treated by Fenton oxidation method. The experiment results show that hair dyeing wastewater is treated by Fenton oxidation in this thesis. Fenton reagent is affected by hair dyeing wastewater, pH reaction time and many other factors. When raw water COD is 3800mg/L and chroma is 1210 times, by using Fenton oxidation method determine best experimental conditions: concentration of H2O2 is 24.5ml（30%H2O2), pH value is 3.0, nH2O2/nFe2+ is 7, reaction time is 60 min. Under the reaction condition , experimental results show that COD and color removal rates were 91.2% and 93.2% in hair dyeing wastewater by Fenton oxidation.
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Navas, Patrick A., Yongqi Yan, Minerva E. Sanchez, Ericka M. Johnson, and George Stamatoyannopoulos. "Talen-Mediated Knock Outs Of Cis and Trans Elements Potentially Involved In Globin Gene Switching." Blood 122, no. 21 (November 15, 2013): 436. http://dx.doi.org/10.1182/blood.v122.21.436.436.
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Abstract Transcription activator-like effector nucleases (TALEN) are engineered proteins used for precise genome editing by generating specific DNA double strand that are repaired by homologous recombination and by non-homologous end joining. TALENs can be used to study gene regulation by deleting putative regulatory elements in the context of the native chromosome and measuring mRNA synthesis. We designed TALENs to delete individual DNAse I-hypersensitive sites (HS) of the β-globin locus control region (LCR) followed by an assessment of globin gene expression and assessment of epigenetic effects in K562 erythroleukemia cells. The β-globin LCR is composed of five HSs and functions as a powerful regulatory element responsible for appropriate levels of the five β-like globin genes during development. Introduction of plasmid DNA encoding a pair of TALENs and targeting individually the flanking region of the HS2, HS3 and HS4 core elements along with a donor 100 base single-stranded oligonucleotide resulted in the successful deletions of each of the three core elements in K562 cells. Individual K562 cells were seeded to produce clones and the mutations were screened by PCR to identify both heterozygous and homozygous clones. The TALEN-mediated 288 bp HS2 core deletion resulted 32 heterozygous (48.5%) and 6 homozygous clones (9.1%) in a total of 66 clones screened. K562 carries three copies of chromosome 11 emphasizing the robustness of TALEN technology to target each of the alleles. In the 199 bp HS3 core deletion, from 113 clones we identified 28 heterozygous (24.8%) and 3 (2.7%) homozygous clones. Lastly, the 301 bp HS4 core deletion yielded 9 homozygous (5.9%) and 12 heterozygous (7.9%) clones from 151 clones screened. Total RNA was isolated from wild-type K562 cells, and from both the heterozygous and homozygous mutant clones and subjected to RNase Protection analysis to quantitate the levels of globin mRNA. Deletion if the HS3 core in K562 cells in a ∼30% reduction in ε-globin mRNA and 2-fold reduction in γ-globin mRNA. A more dramatic effect on globin expression is observed in the HS2 core deletion, as ε- and γ-globin expression is reduced by 2- and 5-fold, respectively. These results suggest that HS2 contributes the majority of the LCR enhancer function in K562 cells. The HS4 core deletion resulted in a modest ∼20% reduction in both ε- and γ-globin expression. TALENs were designed to knockout trans-acting factors implicated to be involved in globin gene regulation and/or globin switching. TALENs bracketing the gene promoters and the first exon of 25 genes encoding either a transcription factor or histone-modifying enzyme were synthesized and post-transfection PCR screens of the transfected pool of K562 cells resulted in the successful identification of 17 gene knockouts. The 17 target genes are PRMT5, LDB1, EIF2AK3, BCL11A, HBSIL, MYB, SOX6, NFE4, NR2F2, NR2C1, NR2C2, CHTOP, NFE2, DNMT3A, RBBP4, MTA2 and MBD2. Single cell clones have been generated by limited dilution of transfected K562 pools and thus far we have identified heterozygous and homozygous clones of 8 of 17 gene knockouts, importantly all clones were identified without selection. The frequency of identifying the knockout clones, represented by the number of clones screened/ number of heterozygous clones/ number of homozygous clones, are as follows: HBS1L (63/3/0), SOX6 (68/13/2), NFE4 (56/13/7), LBD1 (300/2/0), MBD2 (301/0/1), CHTOP (288/66/6), NFE2 (712/44/5) and NR2C1 (96/40/11). The remaining nine gene knockouts and globin gene expression data will be presented at the meetings. These studies highlight a powerful TALEN-mutagenesis platform for target deletions of both cis- and trans-elements to study globin gene switching. TALENs can be synthesized in several days and the screening of the individual clones for the desired knockouts is completed within two weeks. This highly efficient mutagenesis platform will further our understanding of the molecular basis of globin switching. Disclosures: No relevant conflicts of interest to declare.
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Williams, Larissa M., Alicia R. Timme-Laragy, Jared V. Goldstone, Andrew G. McArthur, John J. Stegeman, Roxanna M. Smolowitz, and Mark E. Hahn. "Developmental Expression of the Nfe2-Related Factor (Nrf) Transcription Factor Family in the Zebrafish, Danio rerio." PLoS ONE 8, no. 10 (October 24, 2013): e79574. http://dx.doi.org/10.1371/journal.pone.0079574.
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Lazarevic, Vladimir, Christina Orsmark-Pietras, Henrik Lilljebjörn, Louise Pettersson, Marianne Rissler, Anna Lübking, Mats Ehinger, Gunnar Juliusson, and Thoas Fioretos. "Isolated myelosarcoma is characterized by recurrent NFE2 mutations and concurrent preleukemic clones in the bone marrow." Blood 131, no. 5 (February 1, 2018): 577–81. http://dx.doi.org/10.1182/blood-2017-07-793620.
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Farley, Alison, Sarah Lloyd, Merle Dayton, Christine Biben, Olivia Stonehouse, and Samir Taoudi. "Severe thrombocytopenia is sufficient for fetal and neonatal intracerebral hemorrhage to occur." Blood 138, no. 10 (June 29, 2021): 885–97. http://dx.doi.org/10.1182/blood.2020010111.
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Abstract Intracerebral hemorrhage (ICH) has a devastating impact on the neonatal population. Whether thrombocytopenia is sufficient to cause ICH in neonates is still being debated. In this study, we comprehensively investigated the consequences of severe thrombocytopenia on the integrity of the cerebral vasculature by using 2 orthogonal approaches: by studying embryogenesis in the Nfe2−/− mouse line and by using biologics (anti-GP1Bα antibodies) to induce severe thrombocytopenia at defined times during development. By using a mouse model, we acquired data demonstrating that platelets are required throughout fetal development and into neonatal life for maintaining the integrity of the cerebral vasculature to prevent hemorrhage and that the location of cerebral hemorrhage is dependent on when thrombocytopenia occurs during development. Importantly, this study demonstrates that fetal and neonatal thrombocytopenia-associated ICH occurs within regions of the brain which, in humans, could lead to neurologic damage.
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Zhang, Yong, Jianyong Wan, Shiqiang Liu, Tianmiao Hua, and Qingyan Sun. "Exercise induced improvements in insulin sensitivity are concurrent with reduced NFE2/miR-432-5p and increased FAM3A." Life Sciences 207 (August 2018): 23–29. http://dx.doi.org/10.1016/j.lfs.2018.05.040.
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Ziros, Panos G., Ioannis G. Habeos, Dionysios V. Chartoumpekis, Eleni Ntalampyra, Emmanuel Somm, Cédric O. Renaud, Massimo Bongiovanni, et al. "NFE2-Related Transcription Factor 2 Coordinates Antioxidant Defense with Thyroglobulin Production and Iodination in the Thyroid Gland." Thyroid 28, no. 6 (June 2018): 780–98. http://dx.doi.org/10.1089/thy.2018.0018.
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Li, Bing, Shujun Liu, Lining Miao, and Lu Cai. "Prevention of Diabetic Complications by Activation of Nrf2: Diabetic Cardiomyopathy and Nephropathy." Experimental Diabetes Research 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/216512.
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Diabetic cardiomyopathy and nephropathy are two major causes of death of patients with diabetes. Extra generation of reactive oxygen species (ROS), induced by hyperglycemia, is considered as the main reason for the development of these diabetic complications. Transcription factor, NFE2-related factor 2 (Nrf2), is a master regulator of cellular detoxification response and redox status, and also provides a protective action from various oxidative stresses and damages. Recently we have demonstrated its important role in determining the susceptibility of cells or tissues to diabetes-induced oxidative stress and/or damage. Therefore, this review will specifically summarize the information available regarding the effect of Nrf2 on the diabetic complications with a focus on diabetic cardiomyopathy and nephropathy. Given the feature that Nrf2 is easily induced by several compounds, we also discussed the role of different Nrf2 activators in the prevention or therapy of various diabetic complications. These findings suggest that Nrf2 has a potential application in the clinic setting for diabetic patients in the short future.
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Yang, Weili, Junpei Wang, Zhenzhen Chen, Ji Chen, Yuhong Meng, Liming Chen, Yongsheng Chang, et al. "NFE2 Induces miR-423-5p to Promote Gluconeogenesis and Hyperglycemia by Repressing the Hepatic FAM3A-ATP-Akt Pathway." Diabetes 66, no. 7 (April 14, 2017): 1819–32. http://dx.doi.org/10.2337/db16-1172.
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Amaru Calzada, Ariel, Katia Todoerti, Luca Donadoni, Anna Pellicioli, Giacomo Tuana, Raffaella Gatta, Antonino Neri, et al. "The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2V617F myeloproliferative neoplasm cells." Experimental Hematology 40, no. 8 (August 2012): 634–45. http://dx.doi.org/10.1016/j.exphem.2012.04.007.
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Lichtenberg, Jens, Elisabeth F. Heuston, Cheryl A. Keller, Ross C. Hardison, and David M. Bodine. "Comparison of Expression and Epigenetic Profiles in Human and Mouse Erythropoiesis and Megakaryopoiesis Using a Systems Biology Model." Blood 126, no. 23 (December 3, 2015): 2383. http://dx.doi.org/10.1182/blood.v126.23.2383.2383.
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Abstract To date numerous datasets of gene expression and epigenetic profiles for mouse and human hematopoietic cells have been generated. While individual data sets for a particular cell type have been correlated, no approach exists to harness all expression and epigenetic profiles for the different types of hematopoietic cells. Our goal is to develop a systems biology platform to compare epigenetic profiles of hematopoietic cells towards a better understanding of epigenetic mechanisms governing hematopoiesis. To provide the necessary foundation to support systematic studies of hematopoiesis, we have developed the Systems Biology Repository (SBR, http://sbrblood.nhgri.nih.gov), a data "ranch" for organizing and analyzing transcriptome and epigenome data cells throughout differentiation. To populate SBR, we extracted, curated, annotated, and integrated all human and mouse hematopoietic datasets available through the Encyclopedia of DNA Elements (ENCODE), the Gene Expression Omnibus (GEO) and the Short Read Repository (SRR). These include genome-wide profiles of DNA methylation, histone methylation and acetylation, transcription factor occupancy (ChIPSeq), chromatin accessibility (DNaseISeq, ATACSeq, FAIRESeq), and coding as well as non-coding transcriptional profiles (RNASeq). To demonstrate the utility of SBR, we conducted three different analyses. The first was a vertical study of HistoneSeq (H3K4me1, H3K4me2, H3K4me3, and H3K27ac), DNA methylation and RNASeq profiles during mouse erythroid differentiation. We found a global decrease in DNA methylation from hematopoietic stem and progenitor cells (HSC) through common myeloid progenitors (CMP), erythroid progenitor cells (MEP) and erythroblasts (ERY; 92936 peaks in HSC to 14422 in ERY). The number of expressed genes (using a tags per million cutoff of 10) increased in erythroid progenitors (8901 in HSC to 10778 in CMP and 10670 in MEP) before decreasing in ERY (8654). 62% of histone marks delineating active enhancers (H3K27ac, H3K4me1) are present in both HSC and ERY, while 48% arise de novo during differentiation. In contrast, only 16% of active promoter specific histone marks (H3K4me2, H3K4me3) are present in both HSC and ERY. For a horizontal analysis we compared the DNA methylation, RNASeq, histone modification (H3K4me1, H3K4me2, H3K4me3, and H3K27ac) and transcription factor binding (GATA1 and NFE2) profiles of erythroblasts (ERY) and megakaryocytes (MEG). We found a similar relationship between gene expression and the histone and DNA methylation profiles in each cell type but differences between expression and in transcription factor occupancy. DNA methylation and H3K4me3 was enriched in the gene body of expressed genes (>36%) for both ERY (p ≤ 0.001) and MEG (p ≤ 0.01). In contrast DNA methylation was enriched in the upstream and downstream regions of non-coding RNA genes (p ≤ 0.001). Transcription factor occupancy was cell type specific: 79% of GATA1 sites are in ERY and 72% of NFE2 sites are in MEG. In erythroblasts, DNA methylation and GATA1 binding in the gene body are associated with gene silencing (4 fold difference, p ≤ 0.001), while in megakaryocytes, DNA methylation and NFE2 binding in the gene body are associated with gene activation (8 fold difference, p ≤ 0.001). We used the Mouse Genome Informatics homology map data to perform a cross-species comparison of the expression profiles of mouse and human multipotent progenitors (MPP), proerythroblasts and orthochromatic erythroblasts. We found a total of 5247 genes expressed at significantly different levels (p ≤ 0.001) between human and mouse MPP, while only 2010 genes were expressed at significantly similar levels (p ≤ 0.001). At the proerythroblast and orthochromatic erythroblast stages 7696 genes and 6571 genes were expressed at significantly different levels (p ≤ 0.001) between human and mouse respectively, while 2024 and 2560 genes were expressed at significantly similar levels (p ≤ 0.001). These data are consistent with previous studies showing differences in the transcriptional profiles of mouse and human hematopoietic cells. In summary, SBR provides a foundation to model the genetic and epigenetic landscape in both the mouse and human hematopoietic system, and enables functional correlations to be made between the species. As SBR is expanded to include data from patient cells, it will be possible to model epigenetic changes associated with disease. Disclosures No relevant conflicts of interest to declare.
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Ishitsuka, Yosuke, and Dennis R. Roop. "The Epidermis: Redox Governor of Health and Diseases." Antioxidants 11, no. 1 (December 26, 2021): 47. http://dx.doi.org/10.3390/antiox11010047.
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A functional epithelial barrier necessitates protection against dehydration, and ichthyoses are caused by defects in maintaining the permeability barrier in the stratum corneum (SC), the uppermost protective layer composed of dead cells and secretory materials from the living layer stratum granulosum (SG). We have found that loricrin (LOR) is an essential effector of cornification that occurs in the uppermost layer of SG (SG1). LOR promotes the maturation of corneocytes and extracellular adhesion structure through organizing disulfide cross-linkages, albeit being dispensable for the SC permeability barrier. This review takes psoriasis and AD as the prototype of impaired cornification. Despite exhibiting immunological traits that oppose each other, both conditions share the epidermal differentiation complex as a susceptible locus. We also review recent mechanistic insights on skin diseases, focusing on the Kelch-like erythroid cell-derived protein with the cap “n” collar homology-associated protein 1/NFE2-related factor 2 signaling pathway, as they coordinate the epidermis-intrinsic xenobiotic metabolism. Finally, we refine the theoretical framework of thiol-mediated crosstalk between keratinocytes and leukocytes in the epidermis that was put forward earlier.
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Chan, K., R. Lu, J. C. Chang, and Y. W. Kan. "NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development." Proceedings of the National Academy of Sciences 93, no. 24 (November 26, 1996): 13943–48. http://dx.doi.org/10.1073/pnas.93.24.13943.
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Yu, Kai, Matthew Merguerian, Natalie Deuitch, Erica Bresciani, Joie Davis, Kathleen Craft, Lea C. Cunningham, and Paul P. Liu. "Genomic Landscape of RUNX1-Familial Platelet Disorder with Myeloid Malignancies Reveals Rising Clonal Hematopoiesis." Blood 138, Supplement 1 (November 5, 2021): 1090. http://dx.doi.org/10.1182/blood-2021-151781.
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Abstract Familial platelet disorder with associated myeloid malignancies (FPDMM) is a rare autosomal dominant disease caused by germline RUNX1 mutations. FPDMM patients have defective megakaryocytic development, low platelet counts, prolonged bleeding times, and a life-long risk (20-50%) of developing hematological malignancies. FPDMM is a rare genetic disease in need of comprehensive clinical and genomic studies. In early 2019 we launched a longitudinal natural history study of patients with FPDMM at the NIH Clinical Center and by May 2021 we have enrolled 98 patients and 100 family controls from 55 unrelated families. Genomic data have been generated from 56 patients in 24 families, including whole exome sequencing (WES), RNA-seq, and single-nucleotide polymorphism (SNP) array. We have identified 21 different germline RUNX1 variants among these 24 families, which include lost-of-function mutations throughout the RUNX1 gene, but pathogenic/likely pathogenic missense mutations are mostly clustered in the runt-homology domain (RHD). As an important form of RUNX1 germline mutations, five splice site variants located between exon 4-5 and exon 5-6 were identified in 6 families, which led to the productions of novel transcript forms that are predicted to generate truncated RUNX1 proteins. Large deletions affecting the RUNX1 gene are also common, ranging from 50 Kb to 1.5Mb, which were detected in 8 of the 55 enrolled families. Besides RUNX1, copy number variation (CNV) analysis from both SNP array and WES showed limited CNV events in non-malignant FPDMM patients. In addition, fusion gene analysis did not detect any in-frame fusion gene in these patients, indicating a relatively stable chromosome status in FPDMM patients. Somatic mutation landscape shows that the overall mutation burden in non-malignant FPDMM patients is lower than AML or other cancer types. However, in 13 of the 44 non-malignant patients (30%), somatic mutations were detected in at least one of the reported clonal hematopoiesis of indeterminate potential (CHIP) genes, significantly higher than the general population (4.3%). Moreover, 85% of our patients who carried CHIP mutations are under 65 years of age; in the general population, only 10% of people above 65 years of age and 1% of people under 50 were reported to carry CHIP mutations. Among mutated genes related to clonal hematopoiesis, BCOR is the most frequently mutated gene (5/44) in our FPDMM cohort, which is not a common CHIP gene among the general population. Mutations in known CHIP genes including SF3B1, TET2, and DNMT3A were also found in more than one patient. In addition, sequencing of 5 patients who already developed myeloid malignancies detected somatic mutations in BCOR, TET2, NRAS, KRAS, CTCF, KMT2D, PHF6, and SUZ12. Besides reported CHIP genes or leukemia driver genes, 3 unrelated patients carried somatic mutations in the NFE2 gene, which is essential for regulating erythroid and megakaryocytic maturation and differentiation. Two of the NFE2 mutations are nonsense mutations, and the other is a missense mutation in the important functional domain. NFE2 somatic mutations may play important roles in developing malignancy because 2 of the 3 patients already developed myeloid malignancies. For multiple patients in our cohort, we have sequenced their DNA on multiple timepoints. We have observed patients with expanding clones carrying FKBP8, BCOR or FOXP1 mutations. We have also observed a patient with relatively stable clone(s) with somatic BCOR, DNMT3A, and RUNX1T1, who have been sampled over more than four years. We will follow these somatic mutations through sequencing longitudinally and correlate the findings with clinical observations to see if the dynamic changes of CHIP clones harboring the mutations give rise to MDS or leukemia. In summary, the genomic analysis of our new natural history study demonstrated diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in FPDMM patients. These findings indicate that monitoring the dynamic changes of these CHIP mutations prospectively will benefit patients' clinical management and help us understand possible mechanisms for the progression from FPDMM to myeloid malignancies. Disclosures No relevant conflicts of interest to declare.
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Basu, Paramita, Dayna L. Averitt, Camelia Maier, and Arpita Basu. "The Effects of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (Nrf2) Activation in Preclinical Models of Peripheral Neuropathic Pain." Antioxidants 11, no. 2 (February 21, 2022): 430. http://dx.doi.org/10.3390/antiox11020430.
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Oxidative stress, resulting from an imbalance between the formation of damaging free radicals and availability of protective antioxidants, can contribute to peripheral neuropathic pain conditions. Reactive oxygen and nitrogen species, as well as products of the mitochondrial metabolism such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, are common free radicals. Nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is a transcription factor encoded by the NFE2L2 gene and is a member of the cap ‘n’ collar subfamily of basic region leucine zipper transcription factors. Under normal physiological conditions, Nrf2 remains bound to Kelch-like ECH-associated protein 1 in the cytoplasm that ultimately leads to proteasomal degradation. During peripheral neuropathy, Nrf2 can translocate to the nucleus, where it heterodimerizes with muscle aponeurosis fibromatosis proteins and binds to antioxidant response elements (AREs). It is becoming increasingly clear that the Nrf2 interaction with ARE leads to the transcription of several antioxidative enzymes that can ameliorate neuropathy and neuropathic pain in rodent models. Current evidence indicates that the antinociceptive effects of Nrf2 occur via reducing oxidative stress, neuroinflammation, and mitochondrial dysfunction. Here, we will summarize the preclinical evidence supporting the role of Nrf2 signaling pathways and Nrf2 inducers in alleviating peripheral neuropathic pain.