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Available from: Joseph Borg, Mar 19, 2014
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    • "transcription factor genes in both primitive and definitive erythroid cells (Siatecka and Bieker, 2011; Tallack and Perkins, 2010; Yien and Bieker, 2013). Relatedly, links have been established between mutant or haploinsufficient levels of EKLF and altered human hematology and anemia (Borg et al., 2011; Helias et al., 2013; Siatecka and Bieker, 2011; Singleton et al., 2012). Comparative analysis of expression arrays between EKLF wildtype and EKLF-null fetal liver cells show that a number of genes involved in execution of the terminal erythroid differentiation program are downregulated in the absence of EKLF (Drissen et al., 2005; Hodge et al., 2006; Pilon et al., 2006, 2011; Tallack et al., 2012, 2010). "
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    ABSTRACT: The erythroblastic island provides an important nutritional and survival support niche for efficient erythropoietic differentiation. Island integrity is reliant on adhesive interactions between erythroid and macrophage cells. We show that erythroblastic islands can be formed from single progenitor cells present in differentiating embryoid bodies, and that these correspond to erythro-myeloid progenitors (EMPs) that first appear in the yolk sac of the early developing embryo. Erythroid Krüppel-like factor (EKLF; KLF1), a crucial zinc finger transcription factor, is expressed in the EMPs, and plays an extrinsic role in erythroid maturation by being expressed in the supportive macrophage of the erythroblastic island and regulating relevant genes important for island integrity within these cells. Together with its well-established intrinsic contributions to erythropoiesis, EKLF thus plays a coordinating role between two different cell types whose interaction provides the optimal environment to generate a mature red blood cell.
    Preview · Article · Jun 2014 · Development
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    • "transcription factor genes in both primitive and definitive erythroid cells (Siatecka and Bieker, 2011; Tallack and Perkins, 2010; Yien and Bieker, 2013). Relatedly, links have been established between mutant or haploinsufficient levels of EKLF and altered human hematology and anemia (Borg et al., 2011; Helias et al., 2013; Siatecka and Bieker, 2011; Singleton et al., 2012). Comparative analysis of expression arrays between EKLF wildtype and EKLF-null fetal liver cells show that a number of genes involved in execution of the terminal erythroid differentiation program are downregulated in the absence of EKLF (Drissen et al., 2005; Hodge et al., 2006; Pilon et al., 2006, 2011; Tallack et al., 2012, 2010). "
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    ABSTRACT: KLF1 is an erythroid specific transcription factor that is involved in erythroid lineage commitment, globin switching and terminal red blood cell maturation. Various mutations of KLF1 have been identified in humans, which have led to both benign and pathological phenotypes. The E325K mutation, within the second zinc finger of the KLF1 gene, has been shown to cause a new form of congenital dyserythropoietic anemia (CDA) now labeled as CDA type IV. We report the fourth documented case of this mutation, and propose a clinical diagnostic model to better identify this disease in other patients. Our patient is a Taiwanese child who presented to us at 8years of age with severe hemolytic anemia, splenomegaly, elevated fetal hemoglobin (HbF), iron overload, and dyserythropoiesis in the bone marrow. KLF1 sequence analysis revealed a G-to-A transition in one allele of exon 3, which resulted in the substitution of a glutamate 325 by a lysine. Flow cytometry analysis revealed decreased protein expression of CD44 on the red blood cells, and decreased red blood cell deformability as measured using an ektacytometer. Blood typing revealed his red blood cells to be Co(a-b-), In(b-), LW(ab-) and Lu(b+), even though DNA testing predicted that he would be Co(a+b-) and LW(a+b-). This newly discovered CDA combines features of a hemoglobinopathy, RBC membrane defect and hereditary persistence of HbF (HPFH) which are not seen in the previous types of CDA. Increased awareness of this phenotype may improve the more prompt and accurate diagnosis of these patients.
    Full-text · Article · Mar 2013 · Blood Cells Molecules and Diseases
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    • "Extensive studies have correlated expression of KLF1 and that of numerous erythroid-restricted genes required for progenitor proliferation and differentiation, including cell cycle regulators, synthetic enzymes, and components of the unique membrane and cytoskeletal structures of the mature erythrocyte [13], [14], [15], [16], [17]. Structure-function studies of naturally occurring and experimental KLF1 mutants reveal variable effects on these KLF1-dependent non-globin promoters, that differ significantly from those observed at the β-globin gene [18], [19], [20], [21], [22]. Together, these observations suggest that studies of KLF1 action at non-globin genes may delineate context-specific mechanism(s) of action of this factor, and provide insights into key targets required for effective erythropoiesis. "
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    ABSTRACT: Krüppel-like factor 1(KLF1) is a hematopoietic-specific zinc finger transcription factor essential for erythroid gene expression. In concert with the transacting factor GATA1, KLF1 modulates the coordinate expression of the genes encoding the multi-enzyme heme biosynthetic pathway during erythroid differentiation. To explore the mechanisms underpinning KLF1 action at the gene loci regulating the first 3 steps in this process, we have exploited the K1-ERp erythroid cell line, in which KLF1 translocates rapidly to the nucleus in response to treatment with 4-OH-Tamoxifen (4-OHT). KLF1 acts as a differentiation-independent transcriptional co-regulator of delta-aminolevulinic acid dehydratase (Alad), but not 5-aminolevulinate synthase gene (Alas2) or porphobilinogen deaminase (Pbgd). Similar to its role at the β-globin promoter, KLF1 induces factor recruitment and chromatin changes at the Alad1b promoter in a temporally-specific manner. In contrast to these changes, we observed a distinct mechanism of histone eviction at the Alad1b promoter. Furthermore, KLF1-dependent events were not modulated by GATA1 factor promoter co-occupancy alone. These results not only enhance our understanding of erythroid-specific modulation of heme biosynthetic regulation by KLF1, but provide a model that will facilitate the elucidation of novel KLF1-dependent events at erythroid gene loci that are independent of GATA1 activity.
    Full-text · Article · Oct 2012 · PLoS ONE
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