Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements

Hirano, Ikuo; Suzuki, Norio; Yamazaki, Shun; Sekine, Hiroshi; Minegishi, Naoko; Shimizu, Ritsuko; Yamamoto, Masayuki

doi:10.1128/mcb.00451-16

Cited by 24 publications

(38 citation statements)

References 47 publications

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“…The single HRE found in the LIE is crucial for maximal EPO expression and is probably bound only by HIF-2 in accordance with HIF-2 binding to enhancers [15,17,[22][23][24]. Although some candidates for the kidney-specific HRE have been identified in vitro and in vivo, no definite consensus exists [24][25][26]. Of note, HIF1A knockdown does not suppress EPO expression in the three cell lines studied so far, namely, Hep3B, Kelly, and cortical astrocytes [23,27].…”

Section: Introductionmentioning

confidence: 99%

A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

Tolonen

Heikkilä

Malinen

et al. 2019

Cell. Mol. Life Sci.

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Hypoxia-inducible factor (HIF), an αβ dimer, is the master regulator of oxygen homeostasis with hundreds of hypoxiainducible target genes. Three HIF isoforms differing in the oxygen-sensitive α subunit exist in vertebrates. While HIF-1 and HIF-2 are known transcription activators, HIF-3 has been considered a negative regulator of the hypoxia response pathway. However, the human HIF3A mRNA is subject to complex alternative splicing. It was recently shown that the long HIF-3α variants can form αβ dimers that possess transactivation capacity. Here, we show that overexpression of the long HIF-3α2 variant induces the expression of a subset of genes, including the erythropoietin (EPO) gene, while simultaneous downregulation of all HIF-3α variants by siRNA targeting a shared HIF3A region leads to downregulation of EPO and additional genes. EPO mRNA and protein levels correlated with HIF3A silencing and HIF-3α2 overexpression. Chromatin immunoprecipitation analyses showed that HIF-3α2 binding associated with canonical hypoxia response elements in the promoter regions of EPO. Luciferase reporter assays showed that the identified HIF-3α2 chromatin-binding regions were sufficient to promote transcription by all three HIF-α isoforms. Based on these data, HIF-3α2 is a transcription activator that directly regulates EPO expression.

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Section: Introductionmentioning

confidence: 99%

A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

Tolonen

Heikkilä

Malinen

et al. 2019

Cell. Mol. Life Sci.

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“…HIF2α-inducible Epo -gene expression is critical to maintain systemic oxygen homeostasis through erythropoietic regulation. For REP-cell-specific EPO production, the renal enhancer sequence located 17.4- to 3.6-kb upstream of the mouse Epo gene transcriptional start site is essential, while hepatic EPO production requires the proximal downstream region (Suzuki et al, 2011; Suzuki, 2015; Hirano et al, 2017).…”

Section: Rep Cells: the Major Site Of Erythropoietin Production In Admentioning

confidence: 99%

The Neural Crest as the First Production Site of the Erythroid Growth Factor Erythropoietin

Hirano

Suzuki

2019

Front. Cell Dev. Biol.

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While the neural crest is considered the fourth germ layer that originates a variety of tissues during mammalian development, we recently discovered that some neural crest cells and neuroepithelial cells play a unique role in secreting a vital hematopoietic hormone, erythropoietin (EPO), in mouse embryos. EPO production by the neural crest is transient in mid-stage embryos but essential for the first erythropoiesis in the yolk sac and for sufficient oxygen supply in the whole embryo growing in utero . The site of EPO production shifts from the neural crest to the liver in late embryonic stages, followed by interstitial fibroblasts of the kidneys in adults. Interestingly, the transition of EPO production sites synchronizes with the transition of erythropoietic sites during mouse development from the yolk sac and the fetal liver to the bone marrow. EPO produced by the neural crest and the neuroepithelium is first stored around the production sites and delivered to the yolk sac as an endocrine hormone for erythropoiesis after heartbeat activation. The fact that EPO is produced by some human cell lines derived from neuroblastoma, which mainly originates from the neural crest, provides evidence that the neural crest secretes EPO for primitive erythropoiesis not only in mouse but also in human embryos. Here, we introduce and discuss recent progress in studies on the mechanism of EPO production by the neural crest and its roles in erythropoietic development and in the fate of EPO-producing neural crest cells.

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“…Subsequently the HIF-complex binds hypoxia response elements (HRE) in the promoter/enhancer of a selection of genes, generally increasing their transcription [13][14][15]. This review will give a more in-depth view on the role of HPPs (i.e.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

Watts

Gaete

Rodríguez

et al. 2020

Preprint

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Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO2) as under deprived oxygen (hypoxia) the transcription factor Hypoxia Inducible Factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established HIF-EPO axis, and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond.

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Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements

Cited by 24 publications

References 47 publications

A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

The Neural Crest as the First Production Site of the Erythroid Growth Factor Erythropoietin

Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

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