Extrinsic and intrinsic control by EKLF (KLF1) within a specialized erythroid niche

Xue, Li; Galdass, Mariann; Gnanapragasam, Merlin Nithya; Manwani, Deepa; Bieker, James J.

doi:10.1242/dev.103960

Cited by 33 publications

(60 citation statements)

References 102 publications

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“…11,28,29 It is essential for interaction between developing erythroid cells and the central macrophage of erythroblastic islands, so it is likely to be critical for maturation of erythrocytes in vivo. 49 Many Category 1 genes are occupied by KLF1 in primary human erythroid cells. 37 For example, KLF1 binds to a site ;500 bp upstream of the SLC2A4 gene promoter (supplemental Figure 1B), and the 2 alternative ERMAP gene promoters (supplemental Figure 1C).…”

Section: Klf1 Regulates Genes That Encode Important Blood Groupsmentioning

confidence: 99%

KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome

Magor

Tallack

Gillinder

et al. 2015

Blood

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Key Points• Complete loss of KLF1 function is compatible with life but results in severe nonspherocytic hemolytic anemia and kernicterus.• Human KLF1 regulates most aspects of red cell biology.We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis. (Blood. 2015;125(15):2405-2417

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Section: Klf1 Regulates Genes That Encode Important Blood Groupsmentioning

confidence: 99%

KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome

Magor

Tallack

Gillinder

et al. 2015

Blood

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“…In addition to this concept it is widely accepted that KLF1 is a transcription factor that is highly specific to the erythroid cell lineage [8]. A recent study challenges both these concepts by documenting that mouse embryonic stem cells could generate a clonal line giving rise to both erythroid cells and macrophages, which together formed physical structures that resembled that of erythroblastic islands [111]. It is still unknown, however, the correlation of these macrophages, anatomically and temporally to the erythroblastic islands, whether primitive, fetal, or bone marrow definitive [54].…”

Section: Erythroblastic Islands In Anemia Of Inflammationmentioning

confidence: 99%

The erythroblastic island as an emerging paradigm in the anemia of inflammation

et al. 2015

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Terminal erythroid differentiation occurs in the bone marrow, within specialized niches termed erythroblastic islands. These functional units consist of a macrophage surrounded by differentiating erythroblasts and have been described more than five decades ago but their function in the pathophysiology of erythropoiesis has remained unclear until recently. Here we propose that the central macrophage in the erythroblastic island contributes to the pathophysiology of anemia of inflammation. After introducing erythropoiesis and the interactions between the erythroblasts and the central macrophage within the erythroblastic islands, we will discuss the immunophenotypic characterization of this specific subpopulation of macrophages. We will then integrate these concepts into the currently known pathophysiological drivers of anemia of inflammation and address the role of the central macrophage in this disorder. Finally, as a means of furthering our understanding of the various concepts, we will discuss the differences between murine and rat models with regards to developmental and stress erythropoiesis in an attempt to define a model system representative of human pathophysiology.

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“…Such cooperation is highly conserved in zebrafish and mammals (Miller and Bieker, 1993;Shields and Yang, 1998). Additionally, other factors influence Klf function in vivo, such as epigenetic modification (Chen and Bieker, 2004;Ma et al, 2013) and cellular context (Botella et al, 2002;Eaton et al, 2008;Fischer et al, 2001;Matsumoto et al, 2006;Porcu et al, 2011;Stadhouders et al, 2012;Xue et al, 2014). The functions of several Klf factors during development have been investigated.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis of the zebrafish Klf family identifies two genes important for erythroid maturation

Xue

Gao

Liu

2015

Developmental Biology

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Krüppel-like transcription factors (Klfs), each of which contains a CACCC-box binding domain, have been investigated in a variety of developmental processes, such as angiogenesis, neurogenesis and somatic-cell reprogramming. However, the function and molecular mechanism by which the Klf family acts during developmental hematopoiesis remain elusive. Here, we report identification of 24 Klf family genes in zebrafish using bioinformatics. Gene expression profiling shows that 6 of these genes are expressed in blood and/or vascular endothelial cells during embryogenesis. Loss of function of 2 factors (klf3 or klf6a) leads to a decreased number of mature erythrocytes. Molecular studies indicate that both Klf3 and Klf6a are essential for erythroid cell differentiation and maturation but that these two proteins function in distinct manners. We find that Klf3 inhibits the expression of ferric-chelate reductase 1b (frrs1b), thereby promoting the maturation of erythroid cells, whereas Klf6a controls the erythroid cell cycle by negatively regulating cdkn1a expression to determine the rate of red blood cell proliferation. Taken together, our study provides a global view of the Klf family members that contribute to hematopoiesis in zebrafish and sheds new light on the function and molecular mechanism by which Klf3 and Klf6a act during erythropoiesis in vertebrates.

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Extrinsic and intrinsic control by EKLF (KLF1) within a specialized erythroid niche

Cited by 33 publications

References 102 publications

KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome

KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome

The erythroblastic island as an emerging paradigm in the anemia of inflammation

Genome-wide analysis of the zebrafish Klf family identifies two genes important for erythroid maturation

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