A global role for EKLF in definitive and primitive erythropoiesis

Hodge, Denise J.; Coghill, Elise; Keys, Janelle R.; Maguire, Terry; Hartmann, Belinda; McDowall, Alasdair W.; Weiss, Mitchell J.; Grimmond, Sean M.; Perkins, Andrew C.

doi:10.1182/blood-2005-07-2888

Cited by 195 publications

(305 citation statements)

References 66 publications

(103 reference statements)

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“…Recent studies more directly show that there are other targets, including some in the primitive cell, that are also negatively affected by the absence of EKLF [17][18][19][20]. In the case of Band 4.9 and AHSP expression, this effect is as dramatic in the primitive cell as for β-globin in the definitive cell [17].…”

Section: Discussionmentioning

confidence: 99%

“…EKLF protein can interact with coactivators such as p300/CBP histone acetyltransferases as well as chromatin remodelers such as SWI/SNF to maximally transactivate the β-globin gene [15,16]. EKLF also activates protein-stabilizing, heme biosynthetic pathway, and red cell membrane protein genes in both primitive and definitive cells [17][18][19][20]. Although EKLF predominantly serves as a transcriptional activator, protein-protein interactions between EKLF and corepressors, such as mSin3A and HDAC1 [21], can result in the stage-specific repression of EKLF target genes [22].…”

Section: Introductionmentioning

confidence: 99%

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Non-random subcellular distribution of variant EKLF in erythroid cells

Quadrini¹,

Gruzglin²,

Bieker³

2008

Experimental Cell Research

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EKLF protein plays a prominent role during erythroid development as a nuclear transcription factor. Not surprisingly, exogenous EKLF quickly localizes to the nucleus. However, using two different assays we have unexpectedly found that a substantial proportion of endogenous EKLF resides in the cytoplasm at steady state in all erythroid cells examined. While EKLF localization does not appear to change during either erythroid development or terminal differentiation, we find that the protein displays subtle yet distinct biochemical and functional differences depending on which subcellular compartment it is isolated from, with PEST sequences possibly playing a role in these differences. Localization is unaffected by inhibition of CRM1 activity and the two populations are not differentiated by stability. Heterokaryon assays demonstrate that EKLF is able to shuttle out of the nucleus although its nuclear re-entry is rapid. These studies suggest there is an unexplored role for EKLF in the cytoplasm that is separate from its well-characterized nuclear function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Non-random subcellular distribution of variant EKLF in erythroid cells

Quadrini¹,

Gruzglin²,

Bieker³

2008

Experimental Cell Research

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“…47 KLF1 controls the development and differentiation of erythroid lineage by mediating the switch from expression of fetal ␥-globin to adult ␤-globin and regulates transcription of genes that encode cytoskeletal proteins, heme synthesis enzymes, and blood group antigens. 48,49 KLF1 also regulates the lineage progression of megakaryocyte-erythroid progenitor cells. Failure of terminal erythroid differentiation in KLF1-deficient mice is associated with cell cycle perturbation and reduced expression of E2F2.…”

Section: Genetic Loci Influencing Red Blood Cell Traitsmentioning

confidence: 99%

Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits

Ding

Shameer

Jouni

et al. 2012

Mayo Clinic Proceedings

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Objective: To identify common genetic variants influencing red blood cell (RBC) traits. Patients and Methods: We performed a genomewide association study from June 2008 through July 2011 of hemoglobin, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration in 12,486 patients of European ancestry from the electronic MEdical Records and Genomics (eMERGE) network. We developed an electronic medical record-based algorithm that included individuals who had RBC measurements obtained for clinical care and excluded values measured in the setting of hematopoietic disorders, comorbid conditions, or medications known to affect RBC production or a recent history of blood loss. Results: We identified 4 new genetic loci and replicated 11 loci previously reported to be associated with one or more RBC traits in individuals of European ancestry. Notably, genes present in 3 of the 4 newly identified loci (THRB, PTPLAD1, CDT1) and in 6 of the 11 replicated loci (KLF1, ALDH8A1, CCND3, SPTA1, FBXO7, TFR2/EPO) are implicated in erythroid differentiation and regulation of cell cycle in hematopoietic stem cells. Conclusion: Genes in the erythroid differentiation and cell cycle regulation pathways influence interindividual variation in RBC indices. Our results provide insights into the molecular basis underlying variation in RBC traits.

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“…It was intriguing, therefore, that EKLF is expressed during mouse primitive erythropoiesis, starting early in embryonic development (Southwood et al, 1996). Recently, two separate studies have shown that EKLF plays an essential role in hemoglobin metabolism and membrane stability in both primitive and definitive erythroid cells (Drissen et al, 2005;Hodge et al, 2005). With a view to confirm that this tissue-specific expression pattern was conserved across species, we examined the expression pattern of chicken EKLF mRNA during early development.…”

Section: Discussionmentioning

confidence: 98%

“…EKLF Ϫ/Ϫ mice develop fatal anemia during definitive erythropoiesis and die by day 16 during gestation. Recently, EKLF has been shown to play a role in primitive as well definitive erythropoiesis (Drissen et al, 2005;Hodge et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Identification, characterization, and expression pattern of the chicken EKLF gene

Chervenak¹,

Basu²,

Shin³

et al. 2006

Developmental Dynamics

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EKLF/KLF1 was the first of the Krü ppel-like factors (KLFs) to be identified in mammals and plays an important role in primitive and definitive erythropoiesis. Here, we identify and characterize EKLF in the chicken (cEKLF). The predicted amino acid sequence of the zinc finger region of cEKLF is at least 87.7% similar to mammalian EKLF proteins and is 98.8% and 95% similar to the EKLF orthologues in Xenopus and zebrafish, respectively. During early embryonic development, cEKLF expression is seen in the posterior primitive streak, which gives rise to hematopoietic cells, and then in the blood islands and in circulating blood cells. cEKLF mRNA is expressed in blood cells but not in brain later in chicken embryonic development. cEKLF mRNA is increased in definitive compared with primitive erythropoiesis. The conserved sequence and expression pattern of cEKLF suggests that its function is similar to its orthologues in mammals, Xenopus, and zebrafish.

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A global role for EKLF in definitive and primitive erythropoiesis

Cited by 195 publications

References 66 publications

Non-random subcellular distribution of variant EKLF in erythroid cells

Non-random subcellular distribution of variant EKLF in erythroid cells

Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits

Identification, characterization, and expression pattern of the chicken EKLF gene

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